Pediatric suspension formulation

ABSTRACT

The present disclosure relates to storage-stable proton pump inhibitor (PPI) systems comprising a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, which are constituted with water prior to administration. The present disclosure also relates to oral pharmaceutical suspensions comprising water, a therapeutically effective amount of a PPI or a pharmaceutically acceptable salt thereof, such as omeprazole or a pharmaceutically acceptable salt thereof, and one or more buffering agents.

BACKGROUND

Omeprazole,5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole,inhibits gastric acid secretion. Omeprazole belongs to a class ofantisecretory compounds, the substituted benzimidazoles, that do notexhibit anticholinergic or H₂ histamine antagonist properties. Drugs ofthis class of compounds suppress gastric acid secretion by the specificinhibition of the H⁺/K⁺ ATPase enzyme system at the secretory surface ofthe gastric cell and are called proton pump inhibitors.

Proton pump inhibitors, such as omeprazole, are acid labile and thusthey are rapidly degraded in acidic media, such as the contents of thestomach, but they have an acceptable stability under alkalineconditions. Absorption of orally administered proton pump inhibitors,such as omeprazole, take place in the small intestine.

In order to solve the stability problems of omeprazole in acidicconditions, some omeprazole dosage forms available on the marketincorporate omeprazole as enteric coated granules or pellets in delayedrelease solid oral dosage forms. Examples of such dosage forms include,for example, Losec® and Losec MUPS® which both contain enteric coatedpellets of omeprazole in hard gastro-resistant capsules andgastro-resistant tablets, respectively.

Commonly, pediatric subjects encounter difficulty being administeredsolid oral dosage forms, such as tablets or capsules.

Currently, no oral liquid dosage form of omeprazole is approved inEurope. In the United States, omeprazole powder for oral suspension issold under the trade name Zegerid® which is a white, flavored powderpackaged in single-dose packets which are constituted with water priorto administration. Each packet contains either 20 mg or 40 mg ofomeprazole and 1680 mg of sodium bicarbonate, and the followingexcipients: xylitol, sucrose, sucralose, xanthan gum, and flavorings.One dose of Zegerid® Powder for Oral Suspension contains 460 mg ofsodium (Na⁺). Also available in the United States is a FIRST®-OmeprazoleCompounding Kit that is comprised of omeprazole powder and FIRST-PPI(proton pump inhibitor) Suspension containing artificial strawberryflavor, benzyl alcohol, FD&C Red No. 40, Magnasweet 100 (ammoniumglycyrrhizate), poloxamer 188, propylene glycol, purified water,simethicone emulsion, sodium bicarbonate, sodium citrate (dihydrate),sucralose, and xanthan gum. When compounded, the final product providesa homogenous suspension containing 2 mg/ml of omeprazole in FIRST®-PPISuspension. These omeprazole suspension formulations contain highamounts of sodium which makes these formulations unacceptable forpediatric subjects.

There is a need for a liquid oral omeprazole formulation designedespecially for pediatric subjects.

BRIEF SUMMARY

The present disclosure relates to storage-stable proton pump inhibitor(PPI) systems comprising a therapeutically effective amount of a PPI ora pharmaceutically acceptable salt thereof, such as omeprazole or apharmaceutically acceptable salt thereof, which upon constitution withwater contain sodium at acceptable levels for use in therapy inpediatric subjects. The storage stable PPI systems are specificallysuitable for use in multi-dose dosage forms. The present disclosure alsorelates to oral pharmaceutical suspensions comprising water and apharmaceutically effective amount of a PPI or a pharmaceuticallyacceptable salt thereof, such as omeprazole or a pharmaceuticallyacceptable salt thereof, and one or more buffering agents. The oralpharmaceutical suspension of the present disclosure has an acceptablelevel of buffering capacity for pediatric subjects. In some aspects, thebuffering capacity of the oral pharmaceutical suspensions describedherein is about 2 mEq/ml of the oral suspension.

In one aspect, the present disclosure provides a storage-stableomeprazole system, the system comprising a therapeutically effectiveamount of omeprazole, or a pharmaceutically acceptable salt thereof,wherein the system contains a percentage of moisture of no more thanabout 2.5%, and wherein the system contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight, and further whereinthe storage-stable omeprazole system is constituted with water prior toadministration. In some embodiments of this aspect, the sodium andpotassium are present at a ratio of about 1:3.2 by weight. In someembodiments, the system has a moisture content of about 0.5% to about1.5%.

In some embodiments, the storage-stable omeprazole system furthercomprises a pharmaceutically acceptable desiccant. In some embodiments,the pharmaceutically acceptable desiccant is sodium alginate.

In another aspect, the present disclosure provides a storage-stableomeprazole system, the system comprising (i) a first mixture comprising(a) a therapeutically effective amount of omeprazole, or apharmaceutically acceptable salt thereof, wherein the first mixturecontains a percentage of moisture of no more than about 2.5%; and (ii) asecond mixture comprising a second buffering agent, wherein the secondmixture contains a percentage of moisture of no more than about 2.5%;wherein the first mixture and the second mixture are stored separatelyfrom each other and are mixed together on or just before constitutionwith water, and wherein the system contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight. In some embodiments,the sodium and potassium are present at a ratio of about 1:3.2 byweight. In some embodiments, the first mixture further comprises (b) afirst desiccant. In some embodiments, the first mixture furthercomprises (c) a first buffering agent. In some embodiments, the firstmixture further comprises both (b) the first desiccant and (c) the firstbuffering agent. In some embodiments, the second mixture furthercomprises a second desiccant.

In another aspect, the present disclosure provides a storage-stableomeprazole system formulated in a drug delivery device suitable formulti-dose administration of omeprazole, or the pharmaceuticallyacceptable salt thereof, the system comprising a therapeuticallyeffective amount of omeprazole, or a pharmaceutically acceptable saltthereof, wherein the system contains a percentage of moisture of no morethan about 2.5%, and wherein the system contains no sodium from asodium-containing buffering agent or the system contains sodium andpotassium at a ratio of from about 1:2.6 to about 1:3.4 by weight, andfurther wherein the storage-stable omeprazole system is constituted withwater prior to administration.

In another aspect, the present disclosure provides a storage-stableomeprazole powder system, the system comprising (i) a first powdermixture comprising (a) a therapeutically effective amount of omeprazole,or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and(c) a first buffering agent; and (ii) a second powder mixture comprisingsodium alginate and a second buffering agent, wherein the first powdermixture and the second powder mixture are stored separately from eachother and are mixed together on or just before constitution with water,wherein the system contains sodium and potassium at a ratio of fromabout 1:2.6 to about 1:3.4 by weight. In some embodiments, the sodiumand potassium are present at a ratio of about 1:3.2 by weight.

In another aspect, the present disclosure provides an oralpharmaceutical suspension, comprising water, a pharmaceuticallyeffective amount of omeprazole, or a pharmaceutically acceptable saltthereof, dispersed in the water, and one or more buffering agents, andwherein the suspension contains no sodium from a sodium-containingbuffering agent or the suspension contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight.

In some embodiments, the oral pharmaceutical suspension, compriseswater, a pharmaceutically effective amount of omeprazole, or apharmaceutically acceptable salt thereof, dispersed in the water, andone of more buffering agents, wherein the suspension contains sodium andpotassium at a ratio of from about 1:2.6 to about 1:3.4 by weight.

In some embodiments, the omeprazole, or a pharmaceutically acceptablesalt thereof, in the storage-stable omeprazole systems or oralpharmaceutical suspensions described herein is micronized. In someembodiments, the storage-stable omeprazole systems or oralpharmaceutical suspensions described herein contain a mixture ofmicronized and non-micronized omeprazole or a pharmaceuticallyacceptable salt thereof. In some embodiments, the storage-stableomeprazole system, or specifically the storage-stable omeprazole powdersystem, is provided in a drug delivery device suitable for multi-doseadministration of omeprazole or a pharmaceutically acceptable saltthereof.

In some embodiments, the storage-stable omeprazole system describedherein remains stable at 25° C./60% relative humidity for at least 2years.

In some embodiments, the oral pharmaceutical suspension of the presentdisclosure provides a biphasic pharmacokinetic profile having a firstand second C_(max) and a first and second T_(max) following oraladministration in a subject in need thereof.

In another aspect, the present disclosure provides a method ofinhibiting gastric acid secretion in a subject in need thereof. Incertain embodiments, the method comprises administering to a subject inneed thereof an effective amount of an oral pharmaceutical suspensioncomprising water, a pharmaceutically effective amount of omeprazole, ora pharmaceutically acceptable salt thereof, dispersed in the water, andone or more buffering agents, wherein the suspension contains no sodiumfrom a sodium-containing buffering agent or the suspension containssodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 byweight. In some embodiments, the method comprises administering to asubject in need thereof an effective amount of an oral pharmaceuticalsuspension comprising water, a pharmaceutically effective amount ofomeprazole, or a pharmaceutically acceptable salt thereof, dispersed inthe water, and one or more buffering agents, wherein the suspensioncontains sodium and potassium at a ratio of from about 1:2.6 to about1:3.4 by weight. In some embodiments, the subject is a child. In someembodiments, the suspension comprises from about 1 mg/ml to about 10mg/ml of omeprazole or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a method of preparingan oral pharmaceutical suspension. Typically, the method comprisescombining a first mixture comprising (a) a therapeutically effectiveamount of omeprazole, or a pharmaceutically acceptable salt thereof,wherein the first mixture contains a percentage of moisture of no morethan about 2.5%; with a second mixture comprising a second bufferingagent, wherein the second mixture contains a percentage of moisture ofno more than about 2.5%; to obtain a combined mixture, wherein thecombined mixture contains no sodium from a sodium-containing bufferingagent or the combined mixture contains sodium and potassium at a ratioof from about 1:2.6 to about 1:3.4 by weight; and adding water to thecombined mixture. In some embodiments, the second mixture furthercomprises a second desiccant. In some embodiments, the method comprisescombining a first mixture comprising (a) a therapeutically effectiveamount of omeprazole, or a pharmaceutically acceptable salt thereof,containing a percentage of moisture of no more than about 2.5%; with asecond mixture comprising a second desiccant and a second bufferingagent; to obtain a combined mixture, wherein the combined mixturecontains sodium and potassium at a ratio of from about 1:2.6 to about1:3.4; and adding water to the combined mixture. In some embodiments,the first mixture further comprises (b) a first desiccant. In someembodiments, the first mixture further comprises (c) a first bufferingagent. In some embodiments, the first mixture further comprises both (b)the first desiccant and (c) the first buffering agent.

In another aspect, the present disclosure provides a method ofinhibiting gastric acid secretion, comprising administering to a subjectin need thereof an effective amount of an oral pharmaceutical suspensioncomprising water, a pharmaceutically effective amount of omeprazole, ora pharmaceutically acceptable salt thereof, dispersed in the water, andone or more buffering agents, wherein the suspension contains no sodiumfrom a sodium-containing buffering agent or the suspension containssodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 byweight; and wherein the oral pharmaceutical suspension is prepared bycombining a first mixture comprising (a) a therapeutically effectiveamount of omeprazole, or a pharmaceutically acceptable salt thereof,wherein the first mixture contains a percentage of moisture of no morethan about 2.5%; with a second mixture comprising a second bufferingagent, wherein the second mixture contains a percentage of moisture ofno more than about 2.5%; to obtain a combined mixture, wherein thecombined mixture contains no sodium from a sodium-containing bufferingagent or the combined mixture contains sodium and potassium at a ratioof from about 1:2.6 to about 1:3.4 by weight; and adding water to thecombined mixture. In some embodiments, the second mixture furthercomprises a second desiccant. In some embodiments, the method comprisesadministering to a subject in need thereof an effective amount of anoral pharmaceutical suspension comprising water, a pharmaceuticallyeffective amount of omeprazole, or a pharmaceutically acceptable saltthereof, dispersed in the water, and one or more buffering agents,wherein the suspension contains sodium and potassium at a ratio of fromabout 1:2.6 to about 1:3.4 by weight, wherein the oral pharmaceuticalsuspension is prepared by combining a first mixture comprising (a) atherapeutically effective amount of omeprazole, or a pharmaceuticallyacceptable salt thereof, wherein the first mixture contains a percentageof moisture of no more than about 2.5%; with a second mixture comprisinga second desiccant and a second buffering agent; to obtain a combinedmixture, wherein the combined mixture contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4; and adding water to thecombined mixture. In some embodiments, the first mixture furthercomprises (c) a first buffering agent. In some embodiments, the firstmixture further comprises both (b) the first desiccant and (c) the firstbuffering agent.

Additional embodiments and advantages described herein will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice described herein. Theembodiments and advantages described herein will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts a delivery device suitable for use for storage-stablesystems of the present disclosure.

DETAILED DESCRIPTION

The headings provided herein are not limitations of the various aspectsdescribed herein, which can be defined by reference to the specificationas a whole. It is also to be understood that the terminology used hereinis for the purpose of describing particular aspects only, and is notintended to be limiting, since the scope of the present disclosure willbe limited only by the appended claims.

Definitions

For convenience, the meaning of some terms and phrases used in thespecification, examples, and appended claims are provided below. Unlessstated otherwise, or implicit from context, the following terms andphrases include the meanings provided below. The definitions areprovided to aid in describing particular embodiments, and are notintended to limit the claimed technology, because the scope of thetechnology is limited only by the claims. Unless otherwise defined, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thistechnology belongs. If there is an apparent discrepancy between theusage of a term in the art and its definition provided herein, thedefinition provided within the specification shall prevail.

The articles “a,” “an,” and “the” are used herein to refer to one or tomore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

As used herein, the term “about” means±10% of the specified value,unless otherwise indicated.

The term “at least” prior to a number or series of numbers is understoodto include the number adjacent to the term “at least,” and allsubsequent numbers or integers that could logically be included, asclear from context. When at least is present before a series of numbersor a range, it is understood that “at least” can modify each of thenumbers in the series or range.

The term “no more than” prior to a number or series of numbers isunderstood to include the number adjacent to the term “no more than,”and all preceding numbers or integers that could logically be included,as clear from context. When “no more than” is present before a series ofnumbers or a range, it is understood that “no more than” can modify eachof the numbers in the series or range.

As used herein, the terms “comprises,” “comprising,” “having,”“including,” “containing,” and the like are open-ended terms meaning“including, but not limited to.” To the extent a given embodimentdisclosed herein “comprises” certain elements, it should be understoodthat present disclosure also specifically contemplates and disclosesembodiments that “consist essentially of” those elements and that“consist of” those elements.

The terms “treat,” “treating,” and “treatment” refer to any indicia ofsuccess in the treatment or amelioration of an injury, disease, orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,disease, or condition more tolerable to the patient; slowing in the rateof degeneration or decline; or improving a patient's physical or mentalwell-being. The treatment or amelioration of symptoms can be based onobjective or subject parameters, including the results of a physicalexamination, neuropsychiatric examinations, or psychiatric evaluation.

By an “effective” amount or a “therapeutically effective amount” or “apharmaceutically effective amount” of a drug or pharmacologically activeagent is meant a nontoxic but sufficient amount of the drug or agent toprovide the desired effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like.Thus, it is not always possible to specify an exact “effective amount.”However, an appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable inorganic and organic acids.

The terms “desiccant,” “first desiccant,” and “second desiccant” as usedherein refer to a pharmaceutically acceptable hygroscopic material thatserves to maintain a state of dryness. These desiccants serve toeliminate humidity from the air and they adsorb moisture, therebycreating and sustaining a dry, moisture-free environment. Suitablepharmaceutically acceptable desiccants include, for example, sodiumalginate, starch, and the like.

The term “buffering agent” or “buffer” mean any pharmaceuticallyacceptable weak base or strong base and mixtures thereof which, whenformulated or delivered before, during and/or after the proton pumpinhibitor, such as omeprazole, functions to substantially prevent orinhibit acid degradation of the proton pump inhibitor by gastric acidand to preserve the oral bioavailability of the proton pump inhibitor.

The term “percentage of moisture” refers to a value measured using Losson Drying (LOD) method which involves heating a sample (e.g., sodiumalginate or omeprazole) at 90° C. for 5 minutes and determining the %weight loss.

The term “multi-dose”, as used herein, means that the omeprazole powdersystem, after being constituted with water, can be administered inmultiple doses over a period of time, e.g., for more than 7 days, morethan 14 days, or more than 28 days.

The term “stable” or “storage-stable,” as used herein, refers tochemical stability, wherein not more than 5% w/w of total relatedsubstances, e.g. omeprazole degradation products, are formed on storageat 40° C. and 75% relative humidity (RH) for a period of at least 6months, or at 25° C. and 60% relative humidity for at least 2 years, tothe extent necessary for the sale and use of the omeprazole powdersystem described herein.

As used herein, the phrase “low viscosity grade sodium alginate” refersto sodium alginates having solution viscosities of less than about 100millipascal second (mPa.$) in 3% aqueous solutions. Suitable lowviscosity grade sodium alginates include, for example, Manucol® LB (byFMC Biopolymer).

The term “GERD” refers to gastro-esophageal reflux disease. This is adisease where acid from the stomach escapes into the gullet (the tubewhich connects the throat to the stomach) causing pain, inflammation,and heartburn. In children, the symptoms of the condition can includethe return of stomach contents into the mouth (regurgitation), beingsick (vomiting), and poor weight gain.

The term “PICS” refers to Protection In Situ Constitution System. ThePICS system is a bottle with an integrated cap as shown in FIG. 1 .Omeprazole (or any PPI) containing mixture is in a dry form in the capuntil the point of constitution. A diluent phase, such as the secondmixture described below, is included in the bottle. At the time ofconstitution, the drug loaded mixture is released from the cap into thediluent phase (or the second mixture) by twisting the cap andsubsequently water is added for constitution.

As used herein, the term “child” is a human being between the stages ofbirth and puberty.

The term “puberty” is the process of physical changes through which achild's body matures into an adult body capable of sexual reproduction.On average, girls begin puberty around ages 10-11 and end puberty around15-17; boys begin around ages 11-12 and end around 16-17.

As used herein, the term “infant” is the synonym for “baby,” the veryyoung offspring of a human. The term “infant” is typically applied toyoung children under one year of age.

As used herein, the term “toddler” refers to a child of 12 to 36 monthsold.

As used herein, the term “preadolescent” refers to a person of 10-13years old.

As used herein, the term “adolescent” refers to a person between ages 10and 19.

Storage-Stable Systems Described Herein

Although proton pump inhibitors, such as omeprazole, are widely used fortreatment of gastric acid-mediated disorders in patients, their chemicalinstability in acidic media does not allow formulation of simple aqueousdosage forms for therapy. The present disclosure provides storage-stablePPI systems that upon constitution with water provide oralpharmaceutical PPI suspensions for administering effective amounts of aPPI or a pharmaceutically acceptable salt thereof, such as omeprazole ora pharmaceutically acceptable salt thereof, to a subject in needthereof, while having acceptable levels of sodium for administering topediatric subjects. The oral pharmaceutical suspensions of the presentdisclosure have an acceptable buffering capacity for pediatric subjects.In some embodiments, the buffering capacity of the oral pharmaceuticalsuspensions described herein is about 2 mEq/ml of the oral suspension.This is achieved, for example, by using a balanced buffering systembased on sodium bicarbonate and potassium bicarbonate. In someembodiments, the buffering capacity of the oral pharmaceuticalsuspensions described herein is from about 0.5 mEq/ml to about 4 mEq/mlof the oral suspension. In some embodiments, the buffering capacity ofthe oral pharmaceutical suspensions described herein is from about 1.6mEq/ml to about 2.3 mEq/ml of the oral suspension.

In one aspect, the present disclosure provides a storage-stable PPIsystem (such as a storage-stable omeprazole system), the systemcomprising a therapeutically effective amount of a PPI or apharmaceutically acceptable salt thereof, such as omeprazole, or apharmaceutically acceptable salt thereof, wherein the system contains apercentage of moisture of no more than about 2.5%, and wherein thesystem contains no sodium from a sodium-containing buffering agent orcontains sodium and potassium at a ratio of from about 1:100 to about100:1 by weight, and further wherein the storage-stable PPI system isconstituted with water prior to administration. In certain embodiments,the storage-stable PPI system contains sodium and potassium at a ratioof from about 1:50 to about 50:1 by weight. In certain embodiments, thestorage-stable PPI system contains sodium and potassium at a ratio offrom about 1:10 to about 10:1 by weight. In certain embodiments, thestorage-stable PPI system contains sodium and potassium at a ratio offrom about 1:2 to about 1:5 by weight.

In some embodiments, the storage-stable PPI system (such as astorage-stable omeprazole system) contains no sodium from asodium-containing buffering agent such as sodium carbonate, sodiumbicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate,trisodium phosphate, sodium dihydrogen citrate, disodium hydrogencitrate, trisodium citrate, sodium tetraborate, sodium acetate, disodiumhydrogen phthalate, sodium hydrogen phthalate, sodium bitartrate,disodium tartrate, and sodium succinate.

In some embodiments, the storage-stable PPI system (such as astorage-stable omeprazole system) comprises a therapeutically effectiveamount of a PPI or a pharmaceutically acceptable salt thereof, such asomeprazole or a pharmaceutically acceptable salt thereof, wherein thesystem contains a percentage of moisture of no more than about 2.5%, andwherein the system contains sodium and potassium at a ratio of fromabout 1:2.6 to about 1:3.4 by weight, and further wherein thestorage-stable PPI system is constituted with water prior toadministration. In some embodiments of this aspect, the sodium andpotassium are present at a ratio of about 1:3.2 by weight.

In some embodiments, the storage-stable PPI system (such as astorage-stable omeprazole system) has a moisture content of about 0.5%to about 1.5%. In some embodiments, the storage-stable PPI system (suchas a storage-stable omeprazole system) has a percentage of moisture ofno more than about 1%.

Suitable PPIs (proton pump inhibitors) that can be used in thestorage-stable PPI system described herein include, for example,omeprazole, hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole,dexlansoprazole, rapeprazole, dontoprazole, tenatoprazole, haberprazole,ransoprazole, pariprazole, and leminoprazole, and the pharmaceuticallyacceptable salts thereof. In some embodiments, the PPI is selected fromthe group consisting of omeprazole, esomeprazole, lansoprazole,pantoprazole, dexlandoprazole, rabeprazole, and the pharmaceuticallyacceptable salts thereof. In some embodiments, the PPI is omeprazole oresomeprazole, or a pharmaceutically acceptable salt thereof. Examples ofsuitable PPI pharmaceutically acceptable salts include, for example,sodium, magnesium, calcium and potassium salts, such as for example,omeprazole sodium salt, omeprazole magnesium salt, omeprazole calciumsalt, omeprazole potassium salt, esomeprazole sodium salt, esomeprazolemagnesium salt, esomeprazole calcium salt, and esomeprazole potassiumsalt.

In some embodiments, the PPI is omeprazole or a pharmaceuticallyacceptable salt thereof. In some embodiments, the PPI is omeprazole(i.e., the neutral form of omeprazole without a salt forming cationpresent). In some embodiments, the PPI is esomeprazole or apharmaceutically acceptable salt thereof. In some embodiments, the PPIis esomeprazole (i.e., the neutral form of esomeprazole without a saltforming cation present).

In some embodiments, the storage-stable PPI system further comprises adesiccant. Suitable desiccants include any desiccants that arepharmaceutically acceptable and serve to maintain dryness by eliminatinghumidity from the air and absorbing moisture, thereby creating andsustaining a dry, moisture-free environment for the PPI. Suitablepharmaceutically acceptable desiccants include, for example, sodiumalginate, starch, and the like. In some embodiments, the desiccant issodium alginate. The desiccant can comprise one pharmaceuticallyacceptable desiccant or a mixture of two or more pharmaceuticallyacceptable desiccants.

In some embodiments, the sodium alginate present in the storage-stablePPI systems described herein is dry, i.e., the sodium alginate containsa percentage of moisture of less than about 2%. In some embodiments, thestorage-stable PPI systems comprise dry sodium alginate that has amoisture content of about 0.5% to about 1.5%.

In some embodiments, the sodium alginate present in storage-stable PPIsystems described herein, such as in storage-stable omeprazole systems,is low viscosity grade sodium alginate. Suitable low viscosity gradesodium alginates have solution viscosities of less than about 100millipascal second (mPa.$) in 3% aqueous solutions. Examples of suitablelow viscosity grade sodium alginates include Manucol® LB (by FMCBiopolymer).

In some embodiments, storage-stable PPI systems described herein, suchas storage-stable omeprazole systems, comprise one or more bufferingagents. In some embodiments, storage-stable PPI systems described hereincomprise 1, 2, 3, or 4 buffering agents. In some embodiments,storage-stable PPI systems described herein comprise one bufferingagent. In some embodiments, storage-stable PPI systems described hereincomprise 2 or 3 buffering agents. In some embodiments, storage-stablePPI systems described herein comprise 2 buffering agents.

The storage-stable PPI system described herein, such as thestorage-stable omeprazole system, can comprise any suitable bufferingagent that functions to substantially prevent or inhibit the aciddegradation of the PPI (such as omeprazole or a pharmaceuticallyacceptable salt thereof) by gastric acid sufficient to preserve thebioavailability of the PPI administered. In some embodiments, the one ormore buffering agents are each independently selected from the groupconsisting of alkali metal or alkaline earth metal carbonates,bicarbonates, phosphates, citrates, borates, acetates, phthalates,tartrates, and succinates. In some embodiments, the one or morebuffering agents are each independently selected from sodium orpotassium carbonates, bicarbonates, phosphates, citrates, borates,acetates, phthalates, tartrates, and succinates.

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable omeprazole systems) comprise at least one bufferingagent selected from sodium carbonate, sodium bicarbonate, sodiumdihydrogen phosphate, sodium hydrogen phosphate, trisodium phosphate,sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate,sodium tetraborate, sodium acetate, disodium hydrogen phthalate, sodiumhydrogen phthalate, sodium bitartrate, disodium tartrate, and sodiumsuccinate. In some embodiments, storage-stable PPI systems describedherein (such as storage-stable omeprazole systems) comprise at least onebuffering agent selected from potassium carbonate, potassiumbicarbonate, potassium dihydrogen phosphate, potassium hydrogenphosphate, tripotassium phosphate, potassium dihydrogen citrate,dipotassium hydrogen citrate, tripotassium citrate, potassiumtetraborate, potassium acetate, dipotassium hydrogen phthalate,potassium hydrogen phthalate, potassium bitartrate, dipotassiumtartrate, and potassium succinate.

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable omeprazole systems) comprise no more than onebuffering agent selected from potassium carbonate, potassiumbicarbonate, potassium dihydrogen phosphate, potassium hydrogenphosphate, tripotassium phosphate, potassium dihydrogen citrate,dipotassium hydrogen citrate, tripotassium citrate, potassiumtetraborate, potassium acetate, dipotassium hydrogen phthalate,potassium hydrogen phthalate, potassium bitartrate, dipotassiumtartrate, and potassium succinate. In some embodiments, the onebuffering agent is potassium bicarbonate.

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable omeprazole systems) comprise two or more bufferingagents selected from sodium and potassium carbonates, bicarbonates,phosphates, citrates, borates, acetates, phthalates, tartrates, andsuccinates. In some embodiments, storage-stable PPI systems describedherein comprise both sodium bicarbonate and potassium bicarbonate. Insome embodiments, sodium bicarbonate and potassium bicarbonate arepresent in the system at a ratio of about 1:100 to about 100:1 byweight. In some embodiments, sodium bicarbonate and potassiumbicarbonate are present in the system at a ratio of about 1:50 to about50:1 by weight. In some embodiments, sodium bicarbonate and potassiumbicarbonate are present in the system at a ratio of about 1:10 to about10:1 by weight. In some embodiments, sodium bicarbonate and potassiumbicarbonate are present in the system at a ratio of about 1:2 to about1:5 by weight. In some embodiments, sodium bicarbonate and potassiumbicarbonate are present in the system at a ratio of about 1:2.5 to about1:3.4 by weight. In some embodiments, sodium bicarbonate and potassiumbicarbonate are present at a ratio of about 1:2.7 by weight.

The one or more buffering agents present in the storage-stable PPIsystems described herein (such as storage-stable omeprazole systems) inan amount sufficient to increase gastric fluid pH to a pH that preventsdegradation of at least some of the PPI (such as omeprazole or apharmaceutically acceptable salt thereof) in the gastric fluid.

In some embodiments, the one or more buffering agents provide abuffering capacity of from about 0.5 to about 4 mEq/ml dose ofconstituted storage-stable PPI system described herein with water. Insome embodiments, the one or more buffering agents provide a bufferingcapacity of from about 1.6 to about 2.3 mEq/ml dose of constitutedstorage-stable PPI system described herein with water. In someembodiments, the one or more buffering agents provide a bufferingcapacity of about 2 mEq/ml dose of constituted storage-stable PPI systemdescribed herein with water.

In some embodiments, the one or more buffering agents provide abuffering capacity of from about 0.5 to about 4 mEq/ml dose ofconstituted storage-stable omeprazole system described herein withwater. In some embodiments, the one or more buffering agents provide abuffering capacity of from about 1.6 to about 2.3 mEq/ml dose ofconstituted storage-stable omeprazole system described herein withwater. In some embodiments, the one or more buffering agents provide abuffering capacity of about 2 mEq/ml dose of constituted storage-stableomeprazole system described herein with water.

Storage-stable PPI systems described herein (such as storage-stableomeprazole systems) can be prepared in any suitable multi-particulatedosage form that provides an oral suspension when dispersed in water.Suitable dosage forms include, but are not limited to, a powder, apellet, a granule, a seed, a bead, a spheroid, a microsphere, ormixtures thereof. In some embodiments, storage-stable PPI systemsdescribed herein (such as storage-stable omeprazole systems) are in theform of a powder or a pellet. Suitable powders, pellets, granules,seeds, beads, spheroids, microspheres, and mixtures thereof, can beprepared by conventional pharmacological techniques known in the art.

In some aspects, storage-stable PPI systems described herein (such asstorage-stable omeprazole systems) comprise (i) a first mixturecomprising (a) a therapeutically effective amount of a PPI or apharmaceutically acceptable salt there (such as omeprazole, or apharmaceutically acceptable salt thereof), wherein the first mixturecontains a percentage of moisture of no more than about 2.5%; and (ii) asecond mixture comprising a second buffering agent, wherein the secondmixture contains a percentage of moisture of no more than about 2.5%;wherein the first mixture and the second mixture are stored separatelyfrom each other and are mixed together on or just before constitutionwith water, and wherein the system contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:100 to about 100:1 by weight. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:50 to about 50:1 by weight. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:10 to about 10:1 by weight. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:2 to about 1:5 by weight.

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable omeprazole systems) comprise (i) a first mixturecomprising (a) a therapeutically effective amount of a PPI or apharmaceutically acceptable salt there (such as omeprazole, or apharmaceutically acceptable salt thereof), wherein the first mixturecontains a percentage of moisture of no more than about 2.5%; and (ii) asecond mixture comprising a second buffering agent, wherein the secondmixture contains a percentage of moisture of no more than about 2.5%;wherein the first mixture and the second mixture are stored separatelyfrom each other and are mixed together on or just before constitutionwith water, and wherein the system contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight. In some embodiments,the sodium and potassium are present at a ratio of about 1:3.2 byweight.

In some embodiments, the storage-stable PPI system (such as astorage-stable omeprazole system) contains no sodium from asodium-containing buffering agent.

In some embodiments, the first mixture further comprises (b) a firstdesiccant and/or the second mixture further comprises a seconddesiccant.

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable omeprazole systems) comprise (i) a first mixturecomprising (a) a therapeutically effective amount of a PPI or apharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof), wherein the first mixturecontains a percentage of moisture of no more than about 2.5%; and (ii) asecond mixture comprising a second desiccant and a second bufferingagent, wherein the first mixture and the second mixture are storedseparately from each other and are mixed together on or just beforeconstitution with water, and wherein the system contains sodium andpotassium at a ratio of from about 1:2.6 to about 1:3.4 by weight. Insome embodiments of this aspect, storage-stable PPI systems describedherein (such as storage-stable omeprazole systems) contain sodium andpotassium at a ratio of about 1:3.2 by weight.

In some embodiments, the first mixture and the second mixture eachindependently have a moisture content of about 0.5% to about 1.5%. Insome embodiments, the first mixture and the second mixture have eachindependently a moisture content of about 0.6% to about 1.1%. In someembodiments, the first mixture and the second mixture have eachindependently a moisture content of about 0.5% to about 0.9%. In someembodiments, the first mixture has a moisture content of about 0.5% toabout 1.5% and the second mixture has a moisture content of no more thanabout 1.5%. In some embodiments, the second mixture has a moisturecontent of no more than about 0.5%.

In some embodiments, the first mixture further comprises (b) a firstdesiccant.

In some embodiments, the first mixture further comprises (c) a firstbuffering agent.

In some embodiments, storage-stable PPI systems described herein (suchstorage-stable omeprazole systems) comprise (i) a first mixturecomprising (a) a therapeutically effective amount of a PPI or apharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof), (b) a first desiccant, and(c) a first buffering agent, wherein the first mixture contains apercentage of moisture of no more than about 2.5%; and (ii) a secondmixture comprising a second desiccant and a second buffering agent,wherein the first mixture and the second mixture are stored separatelyfrom each other and are mixed together on or just before constitutionwith water, and wherein the system contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight. In some embodimentsof this aspect, storage-stable PPI systems described herein (such asstorage-stable omeprazole systems) contain sodium and potassium at aratio of about 1:3.2 by weight. In some embodiments, the first mixtureand the second mixture each independently have a moisture content ofabout 0.5% to about 1.5%. In some embodiments, the first mixture and thesecond mixture have each independently a moisture content of about 0.6%to about 1.1%. In some embodiments, the first mixture and the secondmixture have each independently a moisture content of about 0.5% toabout 0.9%. In some embodiments, the first mixture has a moisturecontent of about 0.5% to about 1.5% and the second mixture has amoisture content of no more than about 1.5%. In some embodiments, thesecond mixture has a moisture content of no more than about 0.5%.

The first desiccant and the second desiccant can comprise anypharmaceutically acceptable desiccant as defined above or a mixture oftwo or more pharmaceutically acceptable desiccants. The first desiccantand the second desiccant can be the same or different. In someembodiments, the first desiccant is the same as the second desiccant. Insome embodiments, the first desiccant and the second desiccant aredifferent. In some embodiments, the first desiccant and the seconddesiccant are sodium alginate. In some embodiments, the sodium alginateis dry, i.e., the sodium alginate contains a percentage of moisture ofless than about 2%. In some embodiments, the dry sodium alginate has amoisture content of about 0.5% to about 1.5%.

In some embodiments, the first mixture and the second mixture can be,independently, in the form of a powder, a pellet, a granule, a seed, abead, a spheroid, a microsphere, or mixtures thereof. In someembodiments, the first mixture and the second mixture are eachindependently in the form of a powder or a pellet. In other embodiments,the first mixture and the second mixture can both be in the form of apowder.

In some embodiments, the PPI or a pharmaceutically acceptable saltthereof, such as omeprazole or a pharmaceutically acceptable saltthereof, present in the storage-stable systems described herein ismicronized.

In some embodiments, the PPI or a pharmaceutically acceptable saltthereof is present in the storage-stable systems described herein, is amixture of micronized and non-micronized PPI or a pharmaceuticallyacceptable salt thereof. In some embodiments of this aspect, the PPI ora pharmaceutically acceptable salt thereof comprises from about 30% toabout 70% by weight micronized PPI or the pharmaceutically acceptablesalt and the rest is non-micronized. In some embodiments, the PPI or apharmaceutically acceptable salt thereof is a 1:1 mixture, by weight, ofmicronized and non-micronized PPI or the pharmaceutically acceptablesalt thereof. In some embodiments, the PPI or a pharmaceuticallyacceptable salt thereof is about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or1:9 mixture, by weight of micronized and non-micronized PPI or thepharmaceutically acceptable salt thereof. In some embodiments, the PPIor a pharmaceutically acceptable salt thereof is about a 1:2.3 mixture(i.e., about a mixture) by weight of micronized and non-micronized PPIor the pharmaceutically acceptable salt thereof. In some embodiments,the PPI or a pharmaceutically acceptable salt thereof is about a 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight ofnon-micronized and micronized PPI or the pharmaceutically acceptablesalt thereof. In some embodiments, the PPI or a pharmaceuticallyacceptable salt thereof is about a 1:1.5 mixture (i.e., about a mixture)by weight of non-micronized and micronized PPI or the pharmaceuticallyacceptable salt thereof.

In some embodiments, the omeprazole or a pharmaceutically acceptablesalt thereof present in the storage-stable omeprazole systems describedherein is a mixture of micronized and non-micronized omeprazole or apharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof comprises fromabout 30% to about 70% by weight micronized omeprazole or thepharmaceutically acceptable salt and the rest is non-micronized. In someembodiments, the omeprazole or a pharmaceutically acceptable saltthereof is a 1:1 mixture, by weight, of micronized and non-micronizedomeprazole or the pharmaceutically acceptable salt thereof. In someembodiments, the omeprazole or a pharmaceutically acceptable saltthereof is about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, byweight of micronized and non-micronized omeprazole or thepharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a1:2.3 mixture (i.e., about a 30:70 mixture) by weight of micronized andnon-micronized omeprazole or the pharmaceutically acceptable saltthereof. In some embodiments, the omeprazole or a pharmaceuticallyacceptable salt thereof is about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or1:9 mixture, by weight of non-micronized and micronized omeprazole orthe pharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a1:1.5 mixture (i.e., about a 40:60 mixture) by weight of non-micronizedand micronized omeprazole or the pharmaceutically acceptable saltthereof.

In some embodiments, the first and second buffering agents are presentin an amount sufficient to increase gastric fluid pH to a pH thatprevents degradation of at least some of the PPI or a pharmaceuticallyacceptable salt of omeprazole in the gastric fluid.

In some embodiments, the first and second buffering agents provide abuffering capacity of from about 0.5 to about 4 mEq/ml dose ofconstituted storage-stable PPI system described herein with water. Insome embodiments, the first and second buffering agents provide abuffering capacity of from about 1.6 to about 2.3 mEq/ml dose ofconstituted storage-stable PPI system described herein with water. Insome embodiments, the first and second buffering agents provide abuffering capacity of about 2 mEq/ml dose of constituted storage-stablePPI system described herein with water. In some embodiments, the firstand second buffering agents provide a buffering capacity of about 2.1mEq/ml dose of constituted storage-stable PPI system described hereinwith water.

In some embodiments, the first and second buffering agents provide abuffering capacity of from about 0.5 to about 4 mEq/ml dose ofconstituted storage-stable omeprazole system described herein withwater. In some embodiments, the first and second buffering agentsprovide a buffering capacity of from about 1.6 to about 2.3 mEq/ml doseof constituted storage-stable omeprazole system described herein withwater. In some embodiments, the first and second buffering agentsprovide a buffering capacity of about 2 mEq/ml dose of constitutedstorage-stable omeprazole system described herein with water. In someembodiments, the first and second buffering agents provide a bufferingcapacity of about 2.1 mEq/ml dose of constituted storage-stableomeprazole system described herein with water.

In some embodiments, the first buffering agent and the second bufferingagent can each independently comprise one buffering agent or a mixtureof two or more buffering agents. In some embodiments, the firstbuffering agent and the second buffering agent each independentlycomprises 1, 2, 3, or 4 buffering agents. In some embodiments, the firstbuffering agent and the second buffering agent each independentlycomprises 1, 2, or 3 buffering agents. In some embodiments, the firstbuffering agent and the second buffering agent each independentlycomprises 1 buffering agent or 2 buffering agents.

In some embodiments, the first buffering agent and the second bufferingagent are each independently selected from the group consisting ofalkali metal or alkaline earth metal carbonates, bicarbonates,phosphates, citrates, borates, acetates, phthalates, tartrates,succinates, and mixtures thereof. In some embodiments, the firstbuffering agent and the second buffering agent are each independentlyselected from sodium or potassium carbonates, bicarbonates, phosphates,citrates, borates, acetates, phthalates, tartrates, succinates, andmixtures thereof.

In some embodiments, the first buffering agent is selected from sodiumcarbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodiumhydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate,disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodiumacetate, disodium hydrogen phthalate, sodium hydrogen phthalate, sodiumbitartrate, disodium tartrate, sodium succinate, and mixtures thereof.

In some embodiments, the second buffering agent is selected from sodiumand potassium carbonates, bicarbonates, phosphates, citrates, borates,acetates, phthalates, tartrates, succinates, and mixtures thereof.

In some embodiments, the first buffering agent and the second bufferingagent are each independently selected from the group consisting ofsodium bicarbonate, potassium bicarbonate, and a mixture thereof. Insome embodiments, the first buffering agent is sodium bicarbonate. Insome embodiments, the second buffering agent is a mixture of sodiumbicarbonate and potassium bicarbonate. In some embodiments, the secondmixture comprises about 11% sodium bicarbonate and about 89% potassiumbicarbonate, by weight.

In some embodiments, the first mixture and the second mixture togethercomprise sodium bicarbonate and potassium bicarbonate at a ratio ofabout 1:100 to about 100:1 by weight. In some embodiments, the firstmixture and the second mixture together comprise sodium bicarbonate andpotassium bicarbonate at a ratio of about 1:2.5 to about 1:3.4 byweight. In some embodiments, sodium bicarbonate and potassiumbicarbonate are present at a ratio of about 1:2.7 by weight.

In some embodiments, the first buffering agent and the second bufferingagent are each independently selected from potassium carbonate,potassium bicarbonate, potassium dihydrogen phosphate, potassiumhydrogen phosphate, tripotassium phosphate, potassium hydrogen citrate,dipotassium hydrogen citrate, tripotassium citrate, potassiumtetraborate, potassium acetate, dipotassium hydrogen phthalate,potassium hydrogen phthalate, potassium bitartrate, dipotassiumtartrate, potassium succinate, and a mixture thereof. In someembodiments, the first buffering agent and the second buffering agentare potassium bicarbonate.

Storage-stable PPI systems described herein (such as storage-stableomeprazole systems) can further comprise one or more pharmaceuticallyacceptable excipients including, but not limited to, sweeteners,flavoring agents, preservatives, thickening agents, suspending agents,opacifiers, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, diluents, and antifoaming agents.

Suitable sweeteners include, for example, mannitol, sucrose, fructose,dextrose, isomalt, maltitol, sorbitol, sucralose, acesulfame K,aspartame, cyclamate, saccharin, stevia, sucralose, sodium saccharin,xylitol, or a combination thereof. In some embodiments described herein,the sweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

Suitable flavoring agents include, for example, the following flavors ormixtures thereof: mint, vanilla, banana, apple, orange, pear, peach,strawberry, raspberry, chocolate, lemon, lime, butterscotch, caramel,cherry, and cinnamon. In some embodiments described herein, theflavoring agent is mint flavor, vanilla flavor, or a mixture thereof.

Suitable preservatives include those that are suitable for use inpharmaceutical preparations, including antimicrobial preservatives.Suitable antimicrobial preservatives include, for example, sodiumbenzoate, potassium benzoate, calcium benzoate, methyl paraben sodium,ethyl paraben sodium, and mixtures thereof. In some embodimentsdescribed herein, the preservative is sodium benzoate, methyl parabensodium, or a mixture thereof. In some embodiments, the preservative is amixture of sodium benzoate and methyl paraben sodium.

Suitable thickening agents (or thickeners) include substances which canincrease the viscosity of a liquid without substantially changing itsother properties and which are suitable for oral pharmaceuticalpreparations. Examples of suitable thickeners include, for example,sodium alginate, xanthan gum, guar gum, and locust bean gum. In someembodiments, the thickener is sodium alginate, xanthan gum, or a mixturethereof.

Suitable opacifiers include pharmaceutically acceptable substances addedto a material in order to make the ensuing system opaque, such astitanium dioxide (TiO₂).

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable-omeprazole systems) further comprise a sweetener, aflavoring agent, a preservative, or a mixture thereof.

In some embodiments, the second mixture in storage-stable PPI systemsdescribed herein (such as storage-stable omeprazole systems) furthercomprises a sweetener and a preservative.

In some embodiments, storage-stable PPI systems described herein (suchas storage-stable omeprazole systems) are provided in a drug deliverydevice suitable for multi-dose administration of a PPI or apharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof). In certain embodiments, thedelivery device is as described in U.S. Pat. Nos. 9,051,100, 10,238,803,or U.S. Patent Application Publication No. 2014/0311929, the contents ofwhich are fully incorporated by reference.

In some embodiments, the delivery device is a PICS system. In someaspects, the PICS system is as shown in FIG. 1 .

In some embodiments, the drug delivery device comprises two chambers. Insome embodiments, the two chambers of the drug delivery device can beintegrated. In some embodiments, the second chamber of the drug deliverydevice can be a container body (such as a bottle) and the first chambercan be a cap that can accommodate multi-particulate material and ismounted in the opening of the container body.

In some embodiments, the drug delivery device further comprises a meansfor releasing the contents of the first chamber into the second chamberwithout removing the cap from the drug delivery device.

In some embodiments, a storage-stable PPI system described herein (suchas storage-stable omeprazole system) is provided in a container bodycomprising a cap, wherein (i) the container body contains the secondmixture and has a container opening formed in an upper end thereof; (ii)the cap comprises a cylindrical accommodation portion comprising thefirst mixture and a cap portion sealing an upper end of theaccommodation portion, and wherein (iii) the cap is mounted in thecontainer opening of the container body, wherein when the cap istwisted, the first mixture is released into the container body. In someembodiments, the container body is an amber polyethylene terephthalatebottle and the cap is a polypropylene tamper evident cap.

In certain embodiments, a storage-stable PPI system (such asstorage-stable omeprazole systems) described herein is formulated in adrug delivery device suitable for multi-dose administration of a PPI ora pharmaceutically acceptable salt thereof (such as omeprazole, or thepharmaceutically acceptable salt thereof), wherein the system comprisesa therapeutically effective amount of the PPI or the pharmaceuticallyacceptable salt thereof (such as omeprazole or the pharmaceuticallyacceptable salt thereof), and wherein the system contains a percentageof moisture of no more than about 2.5%, and wherein the system containsno sodium from a sodium-containing buffering agent or the systemcontains sodium and potassium at a ratio of from about 1:100 to about100:1 by weight, and further wherein the storage-stable omeprazolesystem is constituted with water prior to administration. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:50 to about 50:1 by weight. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:10 to about 10:1 by weight. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:2 to about 1:5 by weight. In certainembodiments, the storage-stable PPI system contains sodium and potassiumat a ratio of from about 1:2.6 to about 1:3.4 by weight. In someembodiments of this aspect, the sodium and potassium are present at aratio of about 1:3.2 by weight. In some embodiments, the storage-stablePPI system (such as a storage-stable omeprazole system) contains nosodium from a sodium-containing buffering agent.

In some embodiments, a storage-stable PPI system described herein (suchas storage-stable omeprazole system) remains stable at 25° C./60%relative humidity for at least 2 years.

In some embodiments, the present disclosure provides a storage-stableomeprazole powder system, the system comprising (i) a first powdermixture comprising (a) a therapeutically effective amount of omeprazole,or a pharmaceutically acceptable salt thereof, (b) sodium alginate, and(c) a first buffering agent; and (ii) a second powder mixture comprisingsodium alginate and a second buffering agent, wherein the first powdermixture and the second powder mixture are stored separately from eachother and are mixed together on or just before constitution with water,and wherein the system contains sodium and potassium at a ratio of fromabout 1:2.6 to about 1:3.4 by weight.

In some embodiments, the omeprazole or the pharmaceutically acceptablesalt thereof is micronized. In some embodiments, the omeprazole or thepharmaceutically acceptable salt thereof is a mixture of micronized andnon-micronized omeprazole, or the pharmaceutically acceptable saltthereof. In some embodiments, the omeprazole or the pharmaceuticallyacceptable salt thereof comprises about 30 to about 70% micronizedomeprazole, or the pharmaceutically acceptable salt thereof, and therest of the omeprazole or the pharmaceutically acceptable salt thereofis non-micronized. In some embodiments, the omeprazole is a 1:1 mixture,by weight, of micronized and non-micronized omeprazole or thepharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight of micronizedand non-micronized omeprazole or the pharmaceutically acceptable saltthereof. In some embodiments, the omeprazole or a pharmaceuticallyacceptable salt thereof is about a 1:2.3 mixture (i.e., about a 30:70mixture) by weight of micronized and non-micronized omeprazole or thepharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight ofnon-micronized and micronized omeprazole or the pharmaceuticallyacceptable salt thereof. In some embodiments, the omeprazole or apharmaceutically acceptable salt thereof is about a 1:1.5 mixture (i.e.,about a 40:60 mixture) by weight of non-micronized and micronizedomeprazole or the pharmaceutically acceptable salt thereof.

The first powder mixture can be prepared, for example, by wetgranulation of a mixture of the omeprazole, or a pharmaceuticallyacceptable salt thereof, sodium alginate, and the first buffering agent,drying the granulates, and milling the dry granulates. In someembodiments, the first powder mixture further comprises dry sodiumalginate. A suitable method for preparing the first powder mixture isdescribed in, e.g., U.S. Pat. No. 8,093,271, the contents of which arefully incorporated by reference.

In some embodiments, about 20 to about 30% of the sodium alginatepresent in the first powder mixture are homogenously distributed overthe surface of the first buffering agent. In some embodiments, about 20to about 25% of the sodium alginate present in the first powder mixtureare homogenously distributed over the surface of the first bufferingagent. In some embodiments, the sodium alginate not distributed over thesurface of the first buffering agent in the first powder mixture is dry,i.e., it contains a percentage of moisture of less than about 2%. Insome embodiments, the sodium alginate present in the second powdermixture is dry.

In some embodiments, the dry sodium alginate has a moisture content ofabout 0.5% to about 1.5%. In some embodiments, the sodium alginate islow viscosity grade sodium alginate defined above.

The first buffering agent and the second buffering agents are present inan amount sufficient to increase gastric fluid pH to a pH that preventsdegradation of at least some of the omeprazole, or the pharmaceuticallyacceptable salt thereof, in the gastric fluid. In some aspects, thefirst and second buffering agents provide a buffering capacity of fromabout 0.5 to about 4 mEq/ml dose of constituted storage-stableomeprazole powder system described herein with water. In some aspects,the first and second buffering agents provide a buffering capacity offrom about 1.6 to about 2.3 mEq/ml dose of constituted storage-stableomeprazole powder system described herein with water. In someembodiments, the first and second buffering agents provide a bufferingcapacity of about 2 mEq/ml dose of constituted storage-stable omeprazolepowder system described herein with water.

In some embodiments, the first and second buffering agents present inthe storage-stable omeprazole powder system are each independentlyselected from the group consisting of alkali metal or alkaline earthmetal carbonates, bicarbonates, phosphates, citrates, borates, acetates,phthalates, tartrates, succinates, and mixtures thereof. In someembodiments, the first and second buffering agents are eachindependently selected from the group consisting of sodium bicarbonate,potassium bicarbonate, and a mixture thereof.

In some embodiments, the first buffering agent in the storage-stableomeprazole powder system is sodium bicarbonate.

In some embodiments, the second buffering agent in the storage-stableomeprazole powder system is a mixture of sodium bicarbonate andpotassium bicarbonate.

In some embodiments, the first buffering agent in the storage-stableomeprazole powder system is sodium bicarbonate and the second bufferingagent is a mixture of sodium bicarbonate and potassium bicarbonate. Insome embodiments, the second buffering agent is a mixture of about 11%sodium bicarbonate and about 89% potassium bicarbonate, by weight.

In some embodiments, the first powder mixture and the second powdermixture together in the storage-stable omeprazole powder systemcomprises sodium bicarbonate and potassium bicarbonate at a ratio ofabout 1:2.5 to about 1:3.4 by weight. In some embodiments, sodiumbicarbonate and potassium bicarbonate are present at a ratio of about1:2.7 by weight.

In some embodiments, the first buffering agent in the storage-stableomeprazole powder system is potassium bicarbonate and the secondbuffering agent is potassium bicarbonate.

In some embodiments, the second powder mixture of the storage-stableomeprazole powder system further comprises a sweetener and apreservative. Suitable sweeteners and preservatives as described above.

In some embodiments, the storage-stable omeprazole powder system isprovided in a drug delivery device suitable for multi-doseadministration of omeprazole.

In certain embodiments of this aspect, the drug delivery devicecomprises a first chamber comprising the first powder mixture and asecond chamber comprising the second powder mixture. In certainembodiments, the first chamber and the second chamber can be integrated.In some embodiments, the second chamber of the drug delivery device canbe a container body comprising the second powder mixture (such as abottle) and the first chamber can be a cap comprising the first powdermixture which is mounted in the opening of the container body.

The drug delivery device can further comprise a means for releasing thefirst powder mixture into the second chamber without removing the capfrom the drug delivery device.

In certain embodiments, the storage-stable omeprazole powder system isprovided in a delivery device which is a container body comprising acap. In some embodiments, (i) the container body contains the secondpowder mixture and has a container opening formed in an upper endthereof; (ii) the cap comprises a cylindrical accommodation portioncomprising the first powder mixture and a cap portion sealing an upperend of the accommodation portion, wherein (iii) the cap is mounted inthe container opening of the container body, wherein when the cap istwisted, the first powder mixture is released into the container body.In certain embodiments, the container body is an amber polyethyleneterephthalate bottle and the cap is a polypropylene tamper evident cap.

In certain embodiments, the storage-stable omeprazole powder system ofthe present disclosure remains stable at 40° C./75% relative humidityfor at least 6 months. In some embodiments, the storage-stableomeprazole powder system remains stable at 30° C./65% relative humidityfor at least one year. In some embodiments, the storage-stableomeprazole powder system remains stable at 25° C./60% relative humidityfor at least 2 years.

In some embodiments, the storage-stable PPI system (such as astorage-stable omeprazole system) described herein is enclosed within asealed aluminium foil pouch to minimize ingress of moisture duringstorage of the un-constituted system. In some embodiments, the aluminiumfoil pouch may reduce moisture related degradation of the PPI or apharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof) during storage of thestorage-stable PPI system (such as storage-stable omeprazole system)described herein. In some embodiments, the aluminium foil pouch has apolymer coating inside. The aluminium foil pouches can be sealed byusing a Hawo Heat Sealer (temperature setting 150° C., hold time of oneto two seconds).

Oral Pharmaceutical Suspension

The present disclosure also provides an oral pharmaceutical suspensionfor providing a pharmaceutically effective amount of a PPI, or apharmaceutically acceptable salt thereof, to a subject in need thereof,and especially for a pediatric subject. The oral pharmaceuticalsuspensions described herein contain sodium at acceptable levels for usein therapy in pediatric subjects. The oral pharmaceutical suspensionsare specifically suitable for use in multi-dose dosage forms and arecapable of providing uniform dosages of the PPI or the pharmaceuticallyacceptable salt thereof.

In one aspect, the present disclosure provides an oral pharmaceuticalsuspension, comprising water, a pharmaceutically effective amount of aPPI or a pharmaceutically acceptable salt thereof (such as omeprazole ora pharmaceutically acceptable salt thereof), dispersed in the water, andone of more buffering agents. In certain embodiments, the oralpharmaceutical suspension contains sodium and potassium at a ratio offrom about 1:100 to about 100:1 by weight. In certain embodiments, theoral pharmaceutical suspension contains sodium and potassium at a ratioof from about 1:50 to about 50:1 by weight. In certain embodiments, theoral pharmaceutical suspension contains sodium and potassium at a ratioof from about 1:10 to about 10:1 by weight. In certain embodiments, theoral pharmaceutical suspension contains sodium and potassium at a ratioof from about 1:2 to about 1:5 by weight. In certain embodiments, theoral pharmaceutical suspension contains sodium and potassium at a ratioof from about 1:2.6 to about 1:3.4 by weight. In certain embodiments,the sodium and potassium are present in the oral pharmaceuticalsuspension at a ratio of about 1:3.2 by weight.

In some embodiments, the oral pharmaceutical suspension contains nosodium from a sodium-containing buffering agent such as sodiumcarbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodiumhydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate,disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodiumacetate, disodium hydrogen phthalate, sodium hydrogen phthalate, sodiumbitartrate, disodium tartrate, and sodium succinate.

In some embodiments, oral pharmaceutical suspensions described hereinfurther comprise a stabilizer or a thickener, or both. Suitablethickeners and stabilizers include gelling agents that stabilize liquiddosage forms, such as suspensions. In certain embodiments, the thickeneror stabilizer is sodium alginate. In certain embodiments, the sodiumalginate present is low viscosity grade sodium alginate described above.

In certain embodiments, about 1 ml of the oral pharmaceutical suspensioncontains from about 1 mg to about 10 mg of a PPI or a pharmaceuticallyacceptable salt thereof. In certain embodiments, about 1 ml of the oralpharmaceutical suspension contains from about 1 mg to about 10 mg ofomeprazole, or a pharmaceutically acceptable salt thereof.

In certain embodiments, about 1 ml of the oral pharmaceutical suspensioncontains about 1 mg, about 2 mg, about 4 mg, or about 8 mg of a PPI or apharmaceutically acceptable salt thereof. In certain embodiments, about1 ml of the oral pharmaceutical suspension contains about 1 mg, about 2mg, about 4 mg, or about 8 mg of omeprazole, or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, about 1 ml of the oral pharmaceutical suspensioncontains about 2 mg or about 4 mg of a PPI, or a pharmaceuticallyacceptable salt thereof. In certain embodiments, about 1 ml of the oralpharmaceutical suspension contains about 2 mg or about 4 mg ofomeprazole, or a pharmaceutically acceptable salt thereof.

In some embodiments, oral pharmaceutical suspensions described hereincomprise 1, 2, 3, or 4 buffering agents. In some embodiments, oralpharmaceutical suspensions described herein comprise one bufferingagent. In some embodiments, oral pharmaceutical suspensions describedherein comprise 2 or 3 buffering agents. In some embodiments, oralpharmaceutical suspensions described herein comprise 2 buffering agents.

The oral pharmaceutical suspensions described herein, such as thosecomprising omeprazole or a pharmaceutically acceptable salt thereof, cancomprise any suitable buffering agent that functions to substantiallyprevent or inhibit the acid degradation of the PPI or itspharmaceutically acceptable salt (such as omeprazole of apharmaceutically acceptable salt thereof) by gastric acid sufficient topreserve the bioavailability of the PPI administered. In someembodiments, the one or more buffering agents are each independentlyselected from the group consisting of alkali metal or alkaline earthmetal carbonates, bicarbonates, phosphates, citrates, borates, acetates,phthalates, tartrates, and succinates. In some embodiments, the one ormore buffering agents are each independently selected from sodium orpotassium carbonates, bicarbonates, phosphates, citrates, borates,acetates, phthalates, tartrates, and succinates.

In some embodiments, oral pharmaceutical suspensions described herein(such as suspensions comprising omeprazole or its salt) comprise atleast one buffering agent selected from sodium carbonate, sodiumbicarbonate, sodium dihydrogen phosphate, sodium hydrogen phosphate,trisodium phosphate, sodium dihydrogen citrate, disodium hydrogencitrate, trisodium citrate, sodium tetraborate, sodium acetate, disodiumhydrogen phthalate, sodium hydrogen phthalate, sodium bitartrate,disodium tartrate, and sodium succinate. In some embodiments, oralpharmaceutical suspensions described herein comprise at least onebuffering agent selected from potassium carbonate, potassiumbicarbonate, potassium dihydrogen phosphate, potassium hydrogenphosphate, tripotassium phosphate, potassium dihydrogen citrate,dipotassium hydrogen citrate, tripotassium citrate, potassiumtetraborate, potassium acetate, dipotassium hydrogen phthalate,potassium hydrogen phthalate, potassium bitartrate, dipotassiumtartrate, and potassium succinate.

In some embodiments, oral pharmaceutical suspensions described herein(such as suspensions comprising omeprazole or a pharmaceuticallyacceptable salt thereof) comprise no more than one buffering agentselected from potassium carbonate, potassium bicarbonate, potassiumdihydrogen phosphate, potassium hydrogen phosphate, tripotassiumphosphate, potassium dihydrogen citrate, dipotassium hydrogen citrate,tripotassium citrate, potassium tetraborate, potassium acetate,dipotassium hydrogen phthalate, potassium hydrogen phthalate, potassiumbitartrate, dipotassium tartrate, and potassium succinate. In someembodiments, the one buffering agent is potassium bicarbonate.

In some embodiments, oral pharmaceutical suspensions described herein(such as those comprising omeprazole or a pharmaceutically acceptablesalt thereof) comprise two or more buffering agents selected from sodiumand potassium carbonates, bicarbonates, phosphates, citrates, borates,acetates, phthalates, tartrates, and succinates. In some embodiments,oral pharmaceutical suspensions described herein comprise two bufferingagents. In some embodiments, oral pharmaceutical suspensions describedherein comprise both sodium bicarbonate and potassium bicarbonate.

In some embodiments, sodium bicarbonate and potassium bicarbonate arepresent in the oral pharmaceutical suspension at a ratio of about 1:2.5to about 1:3.4 by weight per 1 ml of the suspension. In someembodiments, sodium bicarbonate and potassium bicarbonate are present ata ratio of about 1:2.7 by weight per 1 ml of the suspension.

In certain embodiments, oral pharmaceutical suspensions described hereincontain sodium and potassium at a ratio of from about 1:100 to about100:1 by weight. In certain embodiments, oral pharmaceutical suspensionsdescribed herein contain sodium and potassium at a ratio of from about1:50 to about 50:1 by weight. In certain embodiments, oralpharmaceutical suspensions described herein contain sodium and potassiumat a ratio of from about 1:10 to about 10:1 by weight. In certainembodiments, oral pharmaceutical suspensions described herein containsodium and potassium at a ratio of from about 1:2 to about 1:5 byweight.

In certain embodiments, oral pharmaceutical suspensions described hereincontain sodium and potassium at a ratio of from about 1:2.6 to about1:3.4 by weight. In certain embodiments, the sodium and potassium arepresent in the oral pharmaceutical suspension at a ratio of about 1:3.2by weight.

The one or more buffering agents present in the oral pharmaceuticalsuspensions described herein in an amount sufficient to increase gastricfluid pH to a pH that prevents degradation of at least some of the PPI(such as omeprazole or a pharmaceutically acceptable salt thereof) inthe gastric fluid.

In certain embodiments, the one or more buffering agents present in theoral pharmaceutical suspension provide a buffering capacity of fromabout 0.5 to about 4 mEq per ml of the suspension. In certainembodiments, the one or more buffering agents present in the oralpharmaceutical suspension provide a buffering capacity of from about 1.6to about 2.3 mEq per ml of the suspension. In certain embodiments, theone or more buffering agents present in the oral pharmaceuticalsuspension provide a buffering capacity of about 2 mEq per ml of thesuspension.

In certain embodiments, oral pharmaceutical suspensions described hereincontain low levels of sodium so that the suspensions are suitable foradministration for pediatric subjects. In some aspects, oralpharmaceutical suspensions described herein comprise about mg to about150 mg of sodium per 5 ml of the suspension. In certain embodiments,about mg to about 100 mg of sodium is present in 5 ml of suspension. Insome embodiments, oral pharmaceutical suspensions described hereincontain about 86 mg of sodium per 5 ml of the suspension. This 5 ml doseis equivalent to 4.3% of the WHO recommended maximum daily dietaryintake of sodium for an adult.

In some embodiments, the PPI or a pharmaceutically acceptable saltthereof, such as omeprazole or a pharmaceutically acceptable saltthereof, present in the oral pharmaceutical suspensions described hereinis micronized.

In some embodiments, the PPI or a pharmaceutically acceptable saltthereof is present in the oral pharmaceutical suspensions describedherein, as a mixture of micronized and non-micronized PPI or apharmaceutically acceptable salt thereof. In some embodiments of thisaspect, the PPI or a pharmaceutically acceptable salt thereof comprisesfrom about 30% to about 70% by weight micronized PPI or thepharmaceutically acceptable salt and the rest is non-micronized. In someembodiments, the PPI or a pharmaceutically acceptable salt thereof is a1:1 mixture, by weight, of micronized and non-micronized PPI or thepharmaceutically acceptable salt thereof. In some embodiments, the PPIor a pharmaceutically acceptable salt thereof is about a 1:2, 1:3, 1:4,1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight of micronized andnon-micronized PPI or the pharmaceutically acceptable salt thereof. Insome embodiments, the PPI or a pharmaceutically acceptable salt thereofis about a 1:2.3 mixture (i.e., about a 30:70 mixture) by weight ofmicronized and non-micronized PPI or the pharmaceutically acceptablesalt thereof. In some embodiments, the PPI or a pharmaceuticallyacceptable salt thereof is about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or1:9 mixture, by weight of non-micronized and micronized PPI or thepharmaceutically acceptable salt thereof. In some embodiments, the PPIor a pharmaceutically acceptable salt thereof is about a 1:1.5 mixture(i.e., about a 40:60 mixture) by weight of non-micronized and micronizedPPI or the pharmaceutically acceptable salt thereof.

In some embodiments, the omeprazole or a pharmaceutically acceptablesalt thereof present in the oral pharmaceutical suspensions describedherein is a mixture of micronized and non-micronized omeprazole or apharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof comprises fromabout 30% to about 70% by weight micronized omeprazole or thepharmaceutically acceptable salt and the rest is non-micronized. In someembodiments, the omeprazole or a pharmaceutically acceptable saltthereof is a 1:1 mixture, by weight, of micronized and non-micronizedomeprazole or the pharmaceutically acceptable salt thereof. In someembodiments, the omeprazole or a pharmaceutically acceptable saltthereof is about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, byweight of micronized and non-micronized omeprazole or thepharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a1:2.3 mixture (i.e., about a 30:70 mixture) by weight of micronized andnon-micronized omeprazole or the pharmaceutically acceptable saltthereof. In some embodiments, the omeprazole or a pharmaceuticallyacceptable salt thereof is about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or1:9 mixture, by weight of non-micronized and micronized omeprazole orthe pharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a1:1.5 mixture (i.e., about a 40:60 mixture) by weight of non-micronizedand micronized omeprazole or the pharmaceutically acceptable saltthereof.

In certain embodiments, the oral pharmaceutical suspension provides abiphasic pharmacokinetic profile having a first and second C_(max) and afirst and second T_(max) following oral administration in a subject inneed thereof.

In certain embodiments, a 5 ml dose of the oral pharmaceuticalsuspension described herein comprises about 10 mg or about 20 mg of aPPI or a pharmaceutically acceptable salt thereof (such as omeprazole ora pharmaceutically acceptable salt thereof), about 200 mg to about 300mg sodium bicarbonate, about 600 mg to about 720 mg of potassiumbicarbonate, and about 100 mg to about 150 mg of sodium alginate. Insome embodiments, the 5 ml dose of the oral pharmaceutical suspensionfurther comprises about 10 mg to about 15 mg methyl paraben sodium saltand about 15 mg to about 30 mg sodium benzoate.

In certain embodiments, a 5 ml dose of the oral pharmaceuticalsuspension described herein comprises about 10 mg or about 20 mgomeprazole, or a pharmaceutically acceptable salt thereof, about 256 mgsodium bicarbonate, about 695 mg of potassium bicarbonate, and about 125mg of sodium alginate.

In some embodiments, the 5 ml dose of the oral pharmaceutical suspensionfurther comprises about 11.45 mg methyl paraben sodium salt and about 25mg sodium benzoate.

Oral pharmaceutical suspensions described herein (such as suspensionscomprising omeprazole or a pharmaceutically acceptable salt thereof) canfurther comprise one or more pharmaceutically acceptable excipientsincluding, but not limited to, sweeteners, flavoring agents,preservatives, thickening agents, suspending agents, opacifiers,disintegration agents, filling agents, surfactants, solubilizers,stabilizers, lubricants, diluents, and antifoaming agents.

Suitable sweeteners include, for example, mannitol, sucrose, fructose,dextrose, isomalt, maltitol, sorbitol, sucralose, acesulfame K,aspartame, cyclamate, saccharin, stevia, sucralose, sodium saccharin,xylitol, or a combination thereof. In some aspects described herein, thesweetener is mannitol, sucralose, or maltitol, or a mixture thereof.

Suitable flavoring agents include, for example, the following flavors ormixtures thereof: mint, vanilla, banana, apple, orange, pear, peach,strawberry, raspberry, chocolate, lemon, lime, butterscotch, caramel,cherry, and cinnamon. In some aspects described herein, the flavoringagent is mint flavor, vanilla flavor, or a mixture thereof.

Suitable preservatives include those that are suitable for use inpharmaceutical preparations, including antimicrobial preservatives.Suitable antimicrobial preservatives include, for example, sodiumbenzoate, potassium benzoate, calcium benzoate, methyl paraben sodium,ethyl paraben sodium, and mixtures thereof. In some aspects describedherein, the preservative is sodium benzoate, methyl paraben sodium, or amixture thereof. In some embodiments, the preservative is a mixture ofsodium benzoate and methyl paraben sodium.

Suitable thickening agents (or thickeners) include substances which canincrease the viscosity of a liquid without substantially changing itsother properties and which are suitable for oral pharmaceuticalpreparations. Examples of suitable thickeners include, for example,sodium alginate, xanthan gum, guar gum, and locust bean gum. In someembodiments, the thickener is sodium alginate, xanthan gum, or a mixturethereof.

Suitable opacifiers include pharmaceutically acceptable substances addedto a material in order to make the ensuing system opaque, such astitanium dioxide (TiO₂).

In some embodiments, oral pharmaceutical suspensions described hereinfurther comprise a sweetener, a flavoring agent, a preservative, or amixture thereof.

The oral pharmaceutical suspensions described herein remain stable forat least one month after constitution with water. The suspensions shouldbe generally stored in a refrigerator (2° C.-8° C.). For up to 2 days,the suspensions can be stored below 25° C.

In some embodiments, the total amount of impurities (i.e., degradationproducts of the PPI, such as omeprazole) formed in the oralpharmaceutical suspension described herein on the day of constitutionwith water (i.e., on Day 0), after being stored at 40° C. and 75%relative humidity (RH) for 3 months before constitution with water, isnot more than 0.16% w/w. In some embodiments, the total amount ofimpurities formed in the oral pharmaceutical suspension on Day 0 is notmore than 0.11% w/w.

In some embodiments, the total amount of impurities formed in the oralpharmaceutical suspension described herein after being stored at 2°C.-8° C. for 28 days after being constituted with water (i.e., on Day28), after being stored at 40° C. and 75% RH for 3 months beforeconstitution with water, is not more than 0.28% w/w. In someembodiments, the total amount of impurities formed in the oralpharmaceutical suspension on Day 28 at 2° C.-8° C. is not more than0.23% w/w.

In some embodiments, the total amount of impurities formed in the oralpharmaceutical suspension described herein after being stored at 2°C.-8° C. for 56 days after being constituted with water (i.e., on Day56), after being stored at 40° C. and 75% RH for 3 months beforeconstitution with water, is not more than 0.38% w/w. In someembodiments, the total amount of impurities formed in the oralpharmaceutical suspension on Day 56 at 2° C.-8° C. is not more than0.33% w/w.

In some embodiments, sodium methyl parahydroxybenzoate is used as apreservative in the storage-stable PPI systems (such as storage-stableomeprazole systems) and oral pharmaceutical suspensions describedherein. In some embodiments, the amount of sodium methylparahydroxybenzoate present in the oral pharmaceutical suspensiondescribed herein on the day of constitution with water (i.e., on Day 0),after being stored at 40° C. and 75% RH for 3 months before constitutionwith water, is at least 94.5% w/w of the total amount originally presentin the storage-stable PPI system described herein (such as astorage-stable omeprazole system). In some embodiments, the amount ofsodium methyl parahydroxybenzoate present in the oral pharmaceuticalsuspension on Day 0 is at least w/w of the total amount originallypresent in the storage-stable PPI system described herein (such as astorage-stable omeprazole system).

In some embodiments, the amount of sodium methyl parahydroxybenzoatepresent in the oral pharmaceutical suspension described herein afterbeing stored at 2° C.-8° C. for 28 days after being constituted withwater (i.e., on Day 28), after being stored at 40° C. and 75% RH for 3months before constitution with water, is at least 92% w/w of the totalamount originally present in the storage-stable PPI system describedherein (such as a storage-stable omeprazole system). In someembodiments, the amount of sodium methyl parahydroxybenzoate present inthe oral pharmaceutical suspension on Day 28 is at least 94% w/w of thetotal amount originally present in the storage-stable PPI systemdescribed herein (such as a storage-stable omeprazole system).

In some embodiments, the amount of sodium methyl parahydroxybenzoatepresent in the oral pharmaceutical suspension described herein afterbeing stored at 2° C.-8° C. for 56 days after being constituted withwater (i.e., on Day 56), after being stored at 40° C. and 75% RH for 3months before constitution with water, is at least 84% w/w of the totalamount originally present in the storage-stable PPI system describedherein (such as a storage-stable omeprazole system). In someembodiments, the amount of sodium methyl parahydroxybenzoate present inthe oral pharmaceutical suspension on Day 56 is at least 86.1% w/w ofthe total amount originally present in the storage-stable PPI systemdescribed herein (such as a storage-stable omeprazole system).

In some embodiments, oral pharmaceutical suspensions described hereinare provided in a drug delivery device suitable for multi-doseadministration of a PPI or a pharmaceutically acceptable salt thereof,such as omeprazole or a pharmaceutically acceptable salt thereof.Suitable drug delivery devices are, for example, as described above inconnection with storage-stable systems described herein.

Methods of Treatment

Omeprazole, and other benzimidazole proton pump inhibitors, arewell-known active substances for the treatment of acid-relateddisorders.

In one aspect, the present disclosure provides a method of inhibitinggastric acid secretion in a subject. The method comprises administeringto a subject in need thereof an effective amount of an oralpharmaceutical suspension of the present disclosure described above.

In certain aspects, the present disclosure provides a method ofinhibiting gastric acid secretion, comprising administering to a subjectin need thereof an effective amount of an oral pharmaceuticalsuspension, wherein the oral pharmaceutical suspension comprises water,a pharmaceutically effective amount of a PPI or a pharmaceuticallyacceptable salt thereof, dispersed in the water, and one or morebuffering agents, and wherein the suspension contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:100 to about 100:1 by weight.

In certain embodiments, the present disclosure provides a method ofinhibiting gastric acid secretion, comprising administering to a subjectin need thereof an effective amount of an oral pharmaceuticalsuspension, wherein the oral pharmaceutical suspension comprises water,a pharmaceutically effective amount of omeprazole or a pharmaceuticallyacceptable salt thereof, dispersed in the water, and one or morebuffering agents, and wherein the suspension contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:100 to about 100:1 by weight.

In certain embodiments, the oral pharmaceutical suspension containssodium and potassium at a ratio of from about 1:50 to about 50:1 byweight. In certain embodiments, the oral pharmaceutical suspensioncontains sodium and potassium at a ratio of from about 1:10 to about10:1 by weight. In certain embodiments, the oral pharmaceuticalsuspension contains sodium and potassium at a ratio of from about 1:2 toabout 1:5 by weight.

In certain embodiments, the present disclosure provides a method ofinhibiting gastric acid secretion, comprising administering to a subjectin need thereof an effective amount of an oral pharmaceuticalsuspension, wherein the oral pharmaceutical suspension comprises water,a pharmaceutically effective amount of a PPI or a pharmaceuticallyacceptable salt thereof, dispersed in the water, and one or morebuffering agents, and wherein the suspension contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight.

In certain embodiments, the present disclosure provides a method ofinhibiting gastric acid secretion, comprising administering to a subjectin need thereof an effective amount of an oral pharmaceuticalsuspension, wherein the oral pharmaceutical suspension comprises water,a pharmaceutically effective amount of omeprazole or a pharmaceuticallyacceptable salt thereof, dispersed in the water, and one or morebuffering agents, and wherein the suspension contains no sodium from asodium-containing buffering agent or contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight.

In some embodiments, the oral pharmaceutical suspension contains nosodium from a sodium-containing buffering agent such as sodiumcarbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodiumhydrogen phosphate, trisodium phosphate, sodium dihydrogen citrate,disodium hydrogen citrate, trisodium citrate, sodium tetraborate, sodiumacetate, disodium hydrogen phthalate, sodium hydrogen phthalate, sodiumbitartrate, disodium tartrate, and sodium succinate.

In certain embodiments, the subject is a child. In some embodiments, thechild is an infant, a toddler, a preadolescent, or an adolescent.

In some embodiments, the method comprises administering an oralpharmaceutical suspension described herein to the subject, wherein about1 ml of the suspension contains from about 1 mg to about 10 mg of a PPIor a pharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof). In some embodiments, about 1ml of the suspension contains about 1 mg, about 2 mg, about 4 mg orabout 8 mg of a PPI or a pharmaceutically acceptable salt thereof (suchas omeprazole or a pharmaceutically acceptable salt thereof). In someembodiments, about 1 ml of the suspension contains about 2 mg of a PPIor a pharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof). In some embodiments, about 1ml of the suspension contains about 4 mg of a PPI or a pharmaceuticallyacceptable salt thereof (such as omeprazole or a pharmaceuticallyacceptable salt thereof).

Oral pharmaceutical suspensions described herein, and especially thosecontaining omeprazole or a pharmaceutically acceptable salt thereof, areuseful in the treatment of, for example, duodenal ulcers, gastriculcers, NSAID-associated gastric and duodenal ulcers, refluxesophagitis, and symptomatic gastro-esophageal reflux disease (GERD).

In one aspect, the present disclosure also provides a method ofinhibiting gastric acid secretion, comprising administering to a subjectin need thereof an effective amount of an oral pharmaceutical suspensioncomprising water, a pharmaceutically effective amount of PPI or apharmaceutically acceptable salt thereof (such as omeprazole, or apharmaceutically acceptable salt thereof), dispersed in the water, andone or more buffering agents, wherein the suspension contains no sodiumfrom a sodium-containing buffering agent or the suspension containssodium and potassium at a ratio of from about 1:100 to about 100:1 byweight; and wherein the oral pharmaceutical suspension is prepared bycombining a first mixture comprising (a) a therapeutically effectiveamount of a PPI or a pharmaceutically acceptable salt thereof (such asomeprazole, or a pharmaceutically acceptable salt thereof), wherein thefirst mixture contains a percentage of moisture of no more than about2.5%; with a second mixture comprising a second buffering agent, whereinthe second mixture contains a percentage of moisture of no more thanabout 2.5%; to obtain a combined mixture, wherein the combined mixturecontains no sodium from a sodium-containing buffering agent or thecombined mixture contains sodium and potassium at a ratio of from about1:100 to about 100:1 by weight; and adding water to the combinedmixture. In certain embodiments, the oral pharmaceutical suspensioncontains sodium and potassium at a ratio of from about 1:50 to about50:1 by weight. In certain embodiments, the oral pharmaceuticalsuspension contains sodium and potassium at a ratio of from about 1:10to about 10:1 by weight. In certain embodiments, the oral pharmaceuticalsuspension contains sodium and potassium at a ratio of from about 1:2 toabout 1:5 by weight. In certain embodiments, the oral pharmaceuticalsuspension contains sodium and potassium at a ratio of from about 1:2.6to about 1:3.4 by weight. In some embodiments, the second mixturefurther comprises a second desiccant.

In certain embodiments, the method of inhibiting gastric acid secretioncomprises administering to a subject in need thereof an effective amountof an oral pharmaceutical suspension comprising water, apharmaceutically effective amount of PPI, or a pharmaceuticallyacceptable salt thereof (such as omeprazole or a pharmaceuticallyacceptable salt thereof), dispersed in the water, and one or morebuffering agents, wherein the suspension contains sodium and potassiumat a ratio of from about 1:2.6 to about 1:3.4 by weight; and wherein theoral pharmaceutical suspension is prepared combining a first mixturecomprising (a) a therapeutically effective amount of a PPI or apharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof), wherein the first mixturecontains a percentage of moisture of no more than about 2.5%; with asecond mixture comprising a second desiccant and a second bufferingagent; to obtain a combined mixture, wherein the combined mixturecontains sodium and potassium at a ratio of from about 1:2.6 to about1:3.4 by weight; and adding water to the combined mixture.

Dosage and Administration

In some aspects, an effective amount of the oral pharmaceuticalsuspension described herein is administered without food on an emptystomach, and preferably at least 30 minutes before a meal. A glass ofwater may be taken after taking a dose. Oral pharmaceutical suspensionsdescribed herein can also be administered to subjects via nasogastric(NG) or percutaneous endoscopic gastrostomy (PEG) tubes.

In some embodiments, oral pharmaceutical suspensions containing about 2mg/ml of a PPI or a pharmaceutically acceptable salt (such as omeprazoleor a pharmaceutically acceptable salt) are suitable for administeringdoses of less than about 15 mg.

In some embodiments, oral pharmaceutical suspensions containing about 4mg/ml of a PPI or a pharmaceutically acceptable salt (such as omeprazoleor a pharmaceutically acceptable salt) are suitable for administeringdoses of about 20 mg or about 40 mg.

A suitable dose for an adult is about 10 mg to about 40 mg once daily.In some aspects, the dose for an adult is about 10 mg, about 20 mg,about 30 mg or about 40 mg once daily.

The doses for children are generally based on their weight.

In some embodiments, a suitable dose of omeprazole or its salt,administered in an oral pharmaceutical suspension to a child of 1 monthto 1 year of age, is about 1 mg/kg once daily.

In some embodiments, a suitable dose of omeprazole or its salt,administered in an oral pharmaceutical suspension to a child of morethan 1 year of age weighing about 10-20 kg, is about 10 mg once daily.In some embodiments, this dose can be increased to 20 mg once daily.

In some embodiments, a suitable dose of omeprazole or its salt,administered in an oral pharmaceutical suspension to a child of morethan 2 years of age and weighing more than about 20 kg, is about 20 mgonce daily. In some embodiments, this dose can be increased to 40 mgonce daily.

In some embodiments, oral pharmaceutical suspensions of the presentdisclosure can be used in combination with another pharmaceutical agentthat is indicated for treating or preventing a gastrointestinaldisorder, such as for example, an anti-bacterial agent, a prokineticagent, a Hz-antagonist, and antacid, or sucralfate, which are commonlyadministered to minimize the pain and/or complications related togastrointestinal disorders.

Methods of Preparing Oral Pharmaceutical Suspensions

In one aspect, the present disclosure provides a method of preparing anoral pharmaceutical suspension described herein. The method comprisescombining a first mixture comprising (a) a therapeutically effectiveamount of a PPI or a pharmaceutically acceptable salt thereof (such asomeprazole, or a pharmaceutically acceptable salt thereof), wherein thefirst mixture contains a percentage of moisture of no more than about2.5%; with a second mixture comprising a second buffering agent, whereinthe second mixture contains a percentage of moisture of no more thanabout 2.5%; to obtain a combined mixture, wherein the combined mixturecontains no sodium from a sodium-containing buffering agent or thecombined mixture contains sodium and potassium at a ratio of from about1:100 to about 100:1 by weight; and adding water to the combinedmixture. In certain embodiments, the combined mixture contains sodiumand potassium at a ratio of from about 1:50 to about 50:1 by weight. Incertain embodiments, the combined mixture contains sodium and potassiumat a ratio of from about 1:10 to about 10:1 by weight. In certainembodiments, the combined mixture contains sodium and potassium at aratio of from about 1:2 to about 1:5 by weight. In certain embodiments,the combined mixture contains sodium and potassium at a ratio of fromabout 1:2.6 to about 1:3.4 by weight. In some embodiments, the combinedmixture contains sodium and potassium at a ratio of about 1:3.2 byweight. In some embodiments, the combined mixture contains no sodiumfrom a sodium-containing buffering agent. In some embodiments, the firstmixture and the second mixture independently has a moisture content ofabout 0.5% to about 1.5%. In some embodiments, the first mixture furthercomprises (b) a first desiccant and/or the second mixture furthercomprises a second desiccant.

In some embodiments, the present disclosure provides a method ofpreparing an oral pharmaceutical suspension, comprising combining afirst mixture comprising (a) a therapeutically effective amount of a PPIor a pharmaceutically acceptable salt thereof (such as omeprazole or apharmaceutically acceptable salt thereof), wherein the first mixturecontains a percentage of moisture of no more than about 2.5%; with asecond mixture comprising a second desiccant and a second bufferingagent; to obtain a combined mixture, wherein the combined mixturecontains sodium and potassium at a ratio of from about 1:2.6 to about1:3.4 by weight; and adding water to the combined mixture. In someembodiments, the sodium and potassium are present at a ratio of about1:3.2 by weight. In some embodiments, the first mixture has a moisturecontent of about 0.5% to about 1.5%.

In some embodiments, the first mixture further comprises (b) a firstdesiccant.

In some embodiments, the first desiccant and the second desiccant aresodium alginate.

In some embodiments, the first mixture further comprises (c) a firstbuffering agent.

In some embodiments, the first mixture and the second mixture are eachindependently in a form of a powder, a pellet, a granule, a seed, abead, a spheroid, a microsphere, or a mixture thereof.

In some embodiments, the PPI or a pharmaceutically acceptable saltthereof (such as omeprazole or a pharmaceutically acceptable saltthereof) present in the oral pharmaceutical suspensions can bemicronized before preparing the oral suspensions. Methods known in theart can be used for micronization of omeprazole or its salts. Forexample, traditional micronization techniques based on friction toreduce particle size can be used, such as milling, bashing and grinding.A typical industrial mill is composed of a cylindrical metallic drumthat usually contains steel spheres. As the drum rotates the spheresinside collide with the particles of the solid, thus crushing themtowards smaller diameters. In the case of grinding, the solid particlesare formed when the grinding units of the device rub against each otherwhile particles of the solid are trapped in between. Methods likecrushing and cutting can also be used for reducing particle diameter.Crushing employs hammer-like tools to break the solid into smallerparticles by means of impact. Cutting uses sharp blades to cut the roughsolid pieces into smaller ones. In addition, modern micronizationmethods that use supercritical fluids in the micronization process canbe used. These methods use supercritical fluids to induce a state ofsupersaturation, which leads to precipitation of individual particles.Suitable techniques include the RESS process (Rapid Expansion ofSupercritical Solutions), the SAS method (Supercritical Anti-Solvent)and the PGSS method (Particles from Gas Saturated Solutions). Thesemodern techniques allow for greater tuneability of the process.Parameters like relative pressure and temperature, solute concentration,and antisolvent to solvent ratio can be varied to adjust to obtain thedesired particle size. The supercritical fluid methods result in finercontrol over particle diameters, distribution of particle size andconsistency of morphology.

In some embodiments, micronized PPI or its pharmaceutically acceptablesalt suitable for use in the oral suspensions described herein is acomposition where 90% or more of the particles have a particle size of20 microns or less (i.e., <20 μm). In some embodiments, the oralpharmaceutical suspensions described herein comprise micronized PPI or apharmaceutically acceptable salt thereof. In some embodiments, 90% ormore of the particles in the micronized PPI or its salt have a particlesize of 20 microns or less.

In some embodiments, micronized omeprazole or its pharmaceuticallyacceptable salt suitable for use in the oral suspensions describedherein is a composition where 90% or more of the particles have aparticle size of 20 microns or less (i.e., <20 μm). In some embodiments,the oral pharmaceutical suspensions described herein comprise micronizedomeprazole. In some embodiments, 90% or more of the particles in themicronized omeprazole have a particle size of 20 microns or less.

In some embodiments, the non-micronized omeprazole is a compositionwhere 95% or more of the particles have a particle size of 425 micronsor less, and 30% or more of the particles have a particle size of 75microns or less.

A PPI and its salts can be prepared by any suitable method known in theart.

Specifically, omeprazole and its salts can be prepared by any suitablemethod known in the art.

In some embodiments, the PPI or a pharmaceutically acceptable salt (suchas omeprazole or a pharmaceutically acceptable salt thereof) used in themethod described herein is micronized.

In some embodiments, the PPI or a pharmaceutically acceptable saltthereof is a mixture of micronized and non-micronized PPI, or thepharmaceutically acceptable salt thereof. In some embodiments, the PPIcomprises about 30 to about 70% micronized PPI, or the pharmaceuticallyacceptable salt thereof, and the rest of the PPI, or thepharmaceutically acceptable salt thereof, is non-micronized. In someembodiments, the PPI is a 1:1 mixture, by weight, of micronized andnon-micronized PPI, or the pharmaceutically acceptable salt thereof. Insome embodiments, the PPI or a pharmaceutically acceptable salt thereofis about a 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weightof micronized and non-micronized PPI or the pharmaceutically acceptablesalt thereof. In some embodiments, the PPI or a pharmaceuticallyacceptable salt thereof is about a 1:2.3 mixture (i.e., about a 30:70mixture) by weight of micronized and non-micronized PPI or thepharmaceutically acceptable salt thereof. In some embodiments, the PPIor a pharmaceutically acceptable salt thereof is about a 1:2, 1:3, 1:4,1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight of non-micronized andmicronized PPI or the pharmaceutically acceptable salt thereof. In someembodiments, the PPI or a pharmaceutically acceptable salt thereof isabout a 1:1.5 mixture (i.e., about a 40:60 mixture) by weight ofnon-micronized and micronized PPI or the pharmaceutically acceptablesalt thereof.

In some embodiments, omeprazole, or the pharmaceutically acceptable saltthereof, is a mixture of micronized and non-micronized omeprazole, orthe pharmaceutically acceptable salt thereof. In some embodiments, theomeprazole comprises about 30 to about 70% micronized omeprazole, or thepharmaceutically acceptable salt thereof, and the rest of theomeprazole, or the pharmaceutically acceptable salt thereof, isnon-micronized. In some embodiments, the omeprazole is a 1:1 mixture, byweight, of micronized and non-micronized omeprazole, or thepharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight of micronizedand non-micronized omeprazole or the pharmaceutically acceptable saltthereof. In some embodiments, the omeprazole or a pharmaceuticallyacceptable salt thereof is about a 1:2.3 mixture (i.e., about a 30:70mixture) by weight of micronized and non-micronized omeprazole or thepharmaceutically acceptable salt thereof. In some embodiments, theomeprazole or a pharmaceutically acceptable salt thereof is about a 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9 mixture, by weight ofnon-micronized and micronized omeprazole or the pharmaceuticallyacceptable salt thereof. In some embodiments, the omeprazole or apharmaceutically acceptable salt thereof is about a 1:1.5 mixture (i.e.,about a 40:60 mixture) by weight of non-micronized and micronizedomeprazole or the pharmaceutically acceptable salt thereof.

The first buffering agent and the second buffering agent used in thepresent method are present in an amount sufficient to increase gastricfluid pH to a pH that prevents degradation of at least some of theomeprazole in the gastric fluid. In some aspects, the first and secondbuffering agents together provide a buffering capacity of from about 0.5mEq/ml to about 4 mEq/ml dose of the suspension. In some aspects, thefirst and second buffering agents together provide a buffering capacityof from about 1.6 mEq/ml to about 2.3 mEq/ml dose of the suspension. Insome aspects, the first and second buffering agents together provide abuffering capacity of about 2 mEq/ml dose of the suspension.

In some embodiments, the first buffering agent and the second bufferingagent are each independently selected from the group consisting ofalkali metal or alkaline earth metal carbonates, bicarbonates,phosphates, citrates, borates, acetates, phthalates, tartrates, andsuccinates. In some embodiments, the first buffering agent and thesecond buffering agent are each independently selected from the groupconsisting of sodium bicarbonate, potassium bicarbonate, and a mixturethereof.

In some embodiments, the first buffering agent is sodium bicarbonate. Inother aspects, the second buffering agent is a mixture of sodiumbicarbonate and potassium bicarbonate. In some embodiments, the secondbuffering agent comprises about 11% sodium bicarbonate and about 89%potassium bicarbonate, by weight.

In some embodiments, the first mixture and the second mixture togethercomprise sodium bicarbonate and potassium bicarbonate at a ratio ofabout 1:2.7 by weight.

In some embodiments, the first buffering agent and the second bufferingagent are potassium bicarbonate.

In some embodiments, the second mixture further comprises a sweetenerand a preservative.

In some embodiments, the method further comprises providing the oralpharmaceutical suspension in a drug delivery device suitable formulti-dose administration of a PPI or a pharmaceutically acceptable saltthereof (such as omeprazole or a pharmaceutically acceptable saltthereof). Suitable drug delivery devices are, for example, as describedabove in connection with storage-stable systems described herein.

The disclosure also provides the following particular embodiments:

-   -   Embodiment 1. A storage-stable omeprazole system, the system        comprising a therapeutically effective amount of omeprazole, or        a pharmaceutically acceptable salt thereof, wherein the system        contains a percentage of moisture of no more than about 2.5%,        and wherein the system contains no sodium from a        sodium-containing buffering agent or the system contains sodium        and potassium at a ratio of from about 1:2.6 to about 1:3.4 by        weight, and further wherein the storage-stable omeprazole system        is constituted with water prior to administration.    -   Embodiment 2. The storage-stable omeprazole system of Embodiment        1, wherein the sodium and potassium are present at a ratio of        about 1:3.2 by weight.    -   Embodiment 3. The storage-stable omeprazole system of Embodiment        1 or 2, wherein the system has a moisture content of about 0.5%        to about 1.5%.    -   Embodiment 4. The storage-stable omeprazole system of any of the        preceding Embodiments, further comprising a pharmaceutically        acceptable desiccant.    -   Embodiment 5. The storage-stable omeprazole system of Embodiment        4, wherein the pharmaceutically acceptable desiccant is sodium        alginate.    -   Embodiment 6. The storage stable omeprazole system of Embodiment        5, wherein the sodium alginate is dry.    -   Embodiment 7. The storage-stable omeprazole system of Embodiment        6, wherein the dry sodium alginate has a moisture content of        about 0.5% to about 1.5%.    -   Embodiment 8. The storage-stable omeprazole system of any one of        Embodiments 5-7, wherein the sodium alginate is low viscosity        grade sodium alginate.    -   Embodiment 9. The storage-stable omeprazole system of any of the        preceding claims, wherein the system comprises one or more        buffering agents each independently selected from the group        consisting of alkali metal or alkaline earth metal carbonates,        bicarbonates, phosphates, citrates, borates, acetates,        phthalates, tartrates, and succinates.    -   Embodiment 10. The storage-stable omeprazole system of any one        of Embodiments 1 and 3-9, wherein the system comprises one        buffering agent which is potassium bicarbonate.    -   Embodiment 11. The storage-stable omeprazole system of        Embodiment 9, wherein the system comprises two or more buffering        agents selected from sodium and potassium carbonates,        bicarbonates, phosphates, citrates, borates, acetates,        phthalates, tartrates, and succinates.    -   Embodiment 12. The storage-stable omeprazole system of        Embodiment 9 or 11, comprising sodium bicarbonate and potassium        bicarbonate.    -   Embodiment 13. The storage-stable omeprazole system of        Embodiment 12, wherein the sodium bicarbonate and potassium        bicarbonate are present at a ratio of about 1:2.7 by weight.    -   Embodiment 14. The storage-stable omeprazole system of any one        of preceding Embodiments, wherein the system is in a form of a        powder, a pellet, a granule, a seed, a bead, a spheroid, a        microsphere, or a mixture thereof    -   Embodiment 15. A storage-stable omeprazole system, the system        comprising (i) a first mixture comprising (a) a therapeutically        effective amount of omeprazole, or a pharmaceutically acceptable        salt thereof, wherein the first mixture contains a percentage of        moisture of no more than about 2.5%; and (ii) a second mixture        comprising a second buffering agent, wherein the second mixture        contains a percentage of moisture of no more than about 2.5%,        wherein the first mixture and the second mixture are stored        separately from each other and are mixed together on or just        before constitution with water, and wherein the system contains        no sodium from a sodium-containing buffering agent or the system        contains sodium and potassium at a ratio of from about 1:2.6 to        about 1:3.4 by weight.    -   Embodiment 16. The storage-stable omeprazole system of        Embodiment 15, wherein the sodium and potassium are present at a        ratio of about 1:3.2 by weight.    -   Embodiment 17. The storage-stable omeprazole system of        Embodiment 15 or 16, wherein the first mixture and/or the second        mixture has a moisture content of about 0.5% to about 1.5%.    -   Embodiment 18. The storage-stable omeprazole system of any one        of Embodiments 15-17, wherein the first mixture further        comprises (b) a first desiccant and/or the second mixture        further comprises a second desiccant.    -   Embodiment 19. The storage-stable omeprazole system of any one        of Embodiments 15-18, wherein the first desiccant and the second        desiccant are sodium alginate.    -   Embodiment 20. The storage-stable omeprazole system of any one        of Embodiments 15-19, wherein the first mixture further        comprises (c) a first buffering agent.    -   Embodiment 21. The storage-stable omeprazole system of any one        of Embodiments 15-20, wherein the first mixture and the second        mixture are each independently in a form of a powder, a pellet,        a granule, a seed, a bead, a spheroid, a microsphere, or a        mixture thereof.    -   Embodiment 22. The storage-stable omeprazole system of any one        of Embodiments 1-21, wherein the omeprazole or the        pharmaceutically acceptable salt thereof is micronized.    -   Embodiment 23. The storage-stable omeprazole system of any one        of Embodiments 1-21, wherein the omeprazole or the        pharmaceutically acceptable salt thereof is a mixture of        micronized and non-micronized omeprazole or the pharmaceutically        acceptable salt thereof.    -   Embodiment 24. The storage-stable omeprazole system of        Embodiment 23, wherein the omeprazole, or the pharmaceutically        acceptable salt thereof, comprises about 30 to about 70%        micronized omeprazole, or the pharmaceutically acceptable salt        thereof, and the rest of the omeprazole, or the pharmaceutically        acceptable salt thereof, is non-micronized.    -   Embodiment 25. The storage-stable omeprazole system of        Embodiment 24, wherein the omeprazole, or the pharmaceutically        acceptable salt thereof, is a 1:1 mixture, by weight, of        micronized and non-micronized omeprazole or the pharmaceutically        acceptable salt thereof    -   Embodiment 26. The storage-stable omeprazole system of any one        of Embodiments 15-25, wherein the first buffering agent and the        second buffering agent are present in an amount sufficient to        increase gastric fluid pH to a pH that prevents degradation of        at least some of the omeprazole in the gastric fluid.    -   Embodiment 27. The storage-stable omeprazole system of any one        of Embodiments 20-26, wherein the first buffering agent and the        second buffering agent together provide a buffering capacity of        about 2 mEq/ml dose of constituted powder with water.    -   Embodiment 28. The storage-stable omeprazole system of any one        of Embodiments 15-27, wherein the first buffering agent and the        second buffering agent are each independently selected from the        group consisting of alkali metal or alkaline earth metal        carbonates, bicarbonates, phosphates, citrates, borates,        acetates, phthalates, tartrates, succinates, and mixtures        thereof    -   Embodiment 29. The storage-stable omeprazole system of any one        of Embodiments 14-28, wherein the first buffering agent and the        second buffering agent are each independently selected from the        group consisting of sodium bicarbonate, potassium bicarbonate,        and a mixture thereof    -   Embodiment 30. The storage-stable omeprazole system of any one        of Embodiments 20-29, wherein the first buffering agent is        sodium bicarbonate.    -   Embodiment 31. The storage-stable omeprazole system of any one        of Embodiments 15-29, wherein the second buffering agent is a        mixture of sodium bicarbonate and potassium bicarbonate.    -   Embodiment 32. The storage-stable omeprazole system of        Embodiment 31, wherein the second buffering agent comprises        about 11% sodium bicarbonate and about 89% potassium        bicarbonate, by weight.    -   Embodiment 33. The storage-stable omeprazole system of any one        of Embodiments 15-31, wherein the first mixture and the second        mixture together comprise sodium bicarbonate and potassium        bicarbonate at a ratio of about 1:2.7 by weight.    -   Embodiment 34. The storage-stable omeprazole system of any one        of Embodiments 15-29, wherein the first buffering agent and the        second buffering agent are potassium bicarbonate.    -   Embodiment 35. The storage-stable omeprazole system of any one        of Embodiments 15-32 and 34, wherein the second mixture further        comprises a sweetener and a preservative.    -   Embodiment 36. The storage-stable omeprazole system of any of        the preceding Embodiments, wherein the storage-stable omeprazole        system is provided in a drug delivery device suitable for        multi-dose administration of omeprazole, or the pharmaceutically        acceptable salt thereof.    -   Embodiment 37. The storage-stable omeprazole system of        Embodiment 36, wherein the drug delivery device comprises two        chambers.    -   Embodiment 38, The storage-stable omeprazole system of        Embodiment 37, wherein the drug delivery device further        comprises a means for releasing the contents of the first        chamber into the second chamber without removing the cap from        the drug delivery device.    -   Embodiment 39. The storage-stable omeprazole system of any one        of Embodiments 15-38, wherein the storage-stable omeprazole        system is provided in a container body comprising a cap,        wherein (i) the container body contains the second mixture and        has a container opening formed in an upper end thereof; (ii) the        cap comprises a cylindrical accommodation portion comprising the        first mixture and a cap portion sealing an upper end of the        accommodation portion, and wherein (iii) the cap is mounted in        the container opening of the container body, wherein when the        cap is twisted, the first mixture is released into the container        body.    -   Embodiment 40. The storage-stable omeprazole system of        Embodiment 39, wherein the container body is an amber        polyethylene terephthalate bottle and the cap is a polypropylene        tamper evident cap.    -   Embodiment 41. The storage-stable omeprazole system of any one        of the preceding Embodiments, wherein the powder system remains        stable at 25° C./60% relative humidity for at least 2 years.    -   Embodiment 42. A storage-stable omeprazole system formulated in        a drug delivery device suitable for multi-dose administration of        omeprazole, or the pharmaceutically acceptable salt thereof, the        system comprising a therapeutically effective amount of        omeprazole, or a pharmaceutically acceptable salt thereof,        wherein the system contains a percentage of moisture of no more        than about 2.5%, and wherein the system contains no sodium from        a sodium-containing buffering agent or the system contains        sodium and potassium at a ratio of from about 1:2.6 to about        1:3.4 by weight, and further wherein the storage-stable        omeprazole system is constituted with water prior to        administration.    -   Embodiment 43. The storage-stable omeprazole system of any one        of Embodiments 1-42, wherein the storage-stable omeprazole        system is enclosed within a sealed aluminium foil pouch.    -   Embodiment 44. A storage-stable omeprazole powder system, the        system comprising (i) a first powder mixture comprising (a) a        therapeutically effective amount of omeprazole, or a        pharmaceutically acceptable salt thereof, (b) sodium alginate,        and (c) a first buffering agent; and (ii) a second powder        mixture comprising sodium alginate and a second buffering agent,        wherein the first powder mixture and the second powder mixture        are stored separately from each other and are mixed together on        or just before constitution with water, and wherein the system        contains sodium and potassium at a ratio of from about 1:2.6 to        about 1:3.4 by weight.    -   Embodiment 45. The storage-stable omeprazole powder system of        Embodiment 44, wherein the omeprazole or the pharmaceutically        acceptable salt thereof is micronized.    -   Embodiment 46. The storage-stable omeprazole powder system of        Embodiment 44 or 45, wherein the omeprazole or the        pharmaceutically acceptable salt thereof is a mixture of        micronized and non-micronized omeprazole, or the        pharmaceutically acceptable salt thereof    -   Embodiment 47. The storage-stable omeprazole powder system of        Embodiment 46, wherein the omeprazole or the pharmaceutically        acceptable salt thereof comprises about 30 to about 70%        micronized omeprazole, or the pharmaceutically acceptable salt        thereof, and the rest of the omeprazole or the pharmaceutically        acceptable salt thereof is non-micronized.    -   Embodiment 48. The storage-stable omeprazole powder system of        Embodiment 46, wherein the omeprazole is a 1:1 mixture, by        weight, of micronized and non-micronized omeprazole or the        pharmaceutically acceptable salt thereof.    -   Embodiment 49. The storage-stable omeprazole powder system of        any one of Embodiments 44-48, wherein the omeprazole, or the        pharmaceutically acceptable salt thereof, and about 20 to about        30% of the sodium alginate present in the first powder mixture        are homogenously distributed over the surface of the first        buffering agent.    -   Embodiment 50. The storage-stable omeprazole powder system of        Embodiment 49, wherein the omeprazole, or the pharmaceutically        acceptable salt thereof, and about 20 to about 25% of the sodium        alginate present in the first powder mixture are homogenously        distributed over the surface of the first buffering agent.    -   Embodiment 51. The storage-stable omeprazole powder system of        Embodiment 49 or 50, wherein the sodium alginate not distributed        over the surface of the first buffering agent in the first        powder mixture is dry.    -   Embodiment 52. The storage-stable omeprazole powder system of        any one of Embodiments 44-51, wherein the sodium alginate        present in the second powder mixture is dry.    -   Embodiment 53. The storage-stable omeprazole powder system of        Embodiment 51 or 52, wherein the dry sodium alginate has a        moisture content of about 0.5% to about 1.5%.    -   Embodiment 54. The storage-stable omeprazole powder system of        any one of Embodiments 44-53, wherein the sodium alginate is low        viscosity grade sodium alginate.    -   Embodiment 55. The storage-stable omeprazole powder system of        any one of Embodiments 44-54, wherein the first and second        buffering agents are present in an amount sufficient to increase        gastric fluid pH to a pH that prevents degradation of at least        some of the omeprazole, or the pharmaceutically acceptable salt        thereof, in the gastric fluid.    -   Embodiment 56. The storage-stable omeprazole powder system of        any one of Embodiments 44-55, wherein the first and second        buffering agents together provide a buffering capacity of about        2 mEq/ml dose of constituted powder with water.    -   Embodiment 57. The storage-stable omeprazole powder system of        any one of Embodiments 44-56, wherein the first and second        buffering agents are each independently selected from the group        consisting of alkali metal or alkaline earth metal carbonates,        bicarbonates, phosphates, citrates, borates, acetates,        phthalates, tartrates, succinates, and mixtures thereof.    -   Embodiment 58. The storage-stable omeprazole powder system of        any one of Embodiments 44-57, wherein the first and second        buffering agents are each independently selected from the group        consisting of sodium bicarbonate, potassium bicarbonate, and a        mixture thereof    -   Embodiment 59. The storage-stable omeprazole powder system of        any one of Embodiments 44-58, wherein the first buffering agent        is sodium bicarbonate.    -   Embodiment 60. The storage-stable omeprazole powder system of        any one of Embodiments 44-59, wherein the second buffering agent        is a mixture of sodium bicarbonate and potassium bicarbonate.    -   Embodiment 61. The storage-stable omeprazole powder system of        Embodiment 60, wherein the mixture comprises about 11% sodium        bicarbonate and about 89% potassium bicarbonate, by weight.    -   Embodiment 62. The storage-stable omeprazole powder system of        any one of Embodiments 44-61, wherein the first powder mixture        and the second powder mixture together comprise sodium        bicarbonate and potassium bicarbonate at a ratio of about 1:2.7        by weight.    -   Embodiment 63. The storage-stable omeprazole powder system of        any one of Embodiments 44-62, wherein the second powder mixture        further comprises a sweetener and a preservative.    -   Embodiment 64. The storage-stable omeprazole powder system of        any one of Embodiments 44-63, wherein the storage-stable        omeprazole powder system is provided in a drug delivery device        suitable for multi-dose administration of omeprazole.    -   Embodiment 65. The storage-stable omeprazole powder system of        Embodiment 64, wherein the drug delivery device comprises a        first chamber comprising the first powder mixture and a second        chamber comprising the second powder mixture.    -   Embodiment 66. The storage-stable omeprazole powder system of        Embodiment 65, wherein the drug delivery device further        comprises a means for releasing the first powder mixture into        the second chamber without removing the cap from the drug        delivery device.    -   Embodiment 67. The storage-stable omeprazole powder system of        any one of Embodiments 44-66, wherein the storage-stable        omeprazole powder system is provided in a container body        comprising a cap, wherein (i) the container body contains the        second powder mixture and has a container opening formed in an        upper end thereof; (ii) the cap comprises a cylindrical        accommodation portion comprising the first powder mixture and a        cap portion sealing an upper end of the accommodation portion,        and wherein (iii) the cap is mounted in the container opening of        the container body, wherein when the cap is twisted, the first        powder mixture is released into the container body.    -   Embodiment 68. The storage-stable omeprazole powder system of        Embodiment 67, wherein the container body is an amber        polyethylene terephthalate bottle and the cap is a polypropylene        tamper evident cap.    -   Embodiment 69. The storage-stable omeprazole powder system of        any one of Embodiments 44-68, wherein the powder system remains        stable at 25° C./60% relative humidity for at least 2 years.    -   Embodiment 70. The storage-stable omeprazole powder system of        any one of Embodiments 44-69, wherein the storage-stable        omeprazole system is enclosed within a sealed aluminium foil        pouch.    -   Embodiment 71. An oral pharmaceutical suspension, comprising        water, a pharmaceutically effective amount of omeprazole, or a        pharmaceutically acceptable salt thereof, dispersed in the        water, and one or more buffering agents, and wherein the        suspension contains no sodium from a sodium-containing buffering        agent or the suspension contains sodium and potassium at a ratio        of from about 1:2.6 to about 1:3.4 by weight.    -   Embodiment 72. The oral pharmaceutical suspension of Embodiment        71, further comprising sodium alginate.    -   Embodiment 73. The oral pharmaceutical suspension of Embodiment        71 or 72, wherein about 1 ml of the suspension contains from        about 1 mg to about 10 mg of omeprazole, or the pharmaceutically        acceptable salt thereof.    -   Embodiment 74. The oral pharmaceutical suspension of Embodiment        73, wherein about 1 ml of the suspension contains about 1 mg,        about 2 mg, about 4 mg, or about 8 mg of omeprazole, or the        pharmaceutically acceptable salt thereof.    -   Embodiment 75. The oral pharmaceutical suspension of Embodiment        74, wherein about 1 ml of the suspension contains about 2 mg or        about 4 mg of omeprazole, or the pharmaceutically acceptable        salt thereof.    -   Embodiment 76. The oral pharmaceutical suspension of any one of        Embodiments 71-75, wherein the one or more buffering agents        provide a buffering capacity of about 2 mEq per ml of the        suspension.    -   Embodiment 77. The oral pharmaceutical suspension of any one of        Embodiments 71-76, wherein the one or more buffering agents are        each independently selected from the group consisting of alkali        metal or alkaline earth metal carbonates, bicarbonates,        phosphates, citrates, borates, acetates, phthalates, tartrates,        and succinates.    -   Embodiment 78. The oral pharmaceutical suspension of any one of        Embodiments 71-77, comprising one buffering agent.    -   Embodiment 79. The oral pharmaceutical suspension of Embodiment        78, wherein the one buffering agent is potassium bicarbonate.    -   Embodiment 80. The oral pharmaceutical suspension of any one of        Embodiments 71-77, comprising a mixture of two buffering agents.    -   Embodiment 81. The oral pharmaceutical suspension of Embodiment        80, comprising a mixture of sodium bicarbonate and potassium        bicarbonate at a ratio of about 1:2.7 by weight.    -   Embodiment 82. The oral pharmaceutical suspension of any one of        Embodiments 71-77 and 80-81, wherein the suspension comprises        about 86 mg of sodium per 5 ml of the suspension.    -   Embodiment 83. The oral pharmaceutical suspension of any one of        Embodiments 71-77 and 80-82, wherein the sodium and potassium        are present at a ratio of about 1:3.2 by weight.    -   Embodiment 84. The oral pharmaceutical suspension of any one of        Embodiments 71-83, wherein the suspension provides a biphasic        pharmacokinetic profile having a first and second C_(max) and a        first and second T_(max) following oral administration in a        subject in need thereof.    -   Embodiment 85. The oral pharmaceutical suspension of any of        Embodiments 66-77, wherein a 5 ml dose comprises about 10 mg or        about 20 mg omeprazole, or the pharmaceutically acceptable salt        thereof, about 256 mg sodium bicarbonate, about 695 mg of        potassium bicarbonate, and about 125 mg of sodium alginate.    -   Embodiment 86. The oral pharmaceutical suspension of Embodiment        78, further comprising about 11.45 mg methyl paraben sodium salt        and about 25 mg sodium benzoate.    -   Embodiment 87. The oral pharmaceutical suspension of any one of        Embodiments 71-86, wherein the omeprazole or the        pharmaceutically acceptable salt thereof is micronized.    -   Embodiment 88. The oral pharmaceutical suspension of any one of        Embodiments 71-86, wherein the omeprazole or the        pharmaceutically acceptable salt thereof is a mixture of        micronized and non-micronized omeprazole, or the        pharmaceutically acceptable salt thereof    -   Embodiment 89. The oral pharmaceutical suspension of Embodiment        88, wherein the omeprazole or the pharmaceutically acceptable        salt thereof comprises about 30 to about 70% micronized        omeprazole, or the pharmaceutically acceptable salt thereof, and        the rest of the omeprazole or the pharmaceutically acceptable        salt thereof is non-micronized.    -   Embodiment 90. The oral pharmaceutical suspension of Embodiment        88, wherein the omeprazole is a 1:1 mixture, by weight, of        micronized and non-micronized omeprazole or the pharmaceutically        acceptable salt thereof.    -   Embodiment 91. The oral pharmaceutical suspension of any one of        Embodiments 71-90, wherein the suspension is provided in a drug        delivery device suitable for multi-dose administration of        omeprazole.    -   Embodiment 92. A method of inhibiting gastric acid secretion,        comprising administering to a subject in need thereof an        effective amount of the oral pharmaceutical suspension of any        one of Embodiments 71-91.    -   Embodiment 93. The method of Embodiment 92, wherein the subject        is a child.    -   Embodiment 94. The method of Embodiment 93, wherein the child is        an infant, a toddler, a preadolescent, or an adolescent.    -   Embodiment 95. The method of any one of Embodiments 92-94,        wherein about 1 ml of the suspension contains from about 1 mg to        about 10 mg of omeprazole, or the pharmaceutically acceptable        salt thereof.    -   Embodiment 96. The method of any one of Embodiments 92-95,        wherein 1 ml of the suspension contains about 1 mg, about 2 mg,        about 4 mg or about 8 mg of omeprazole, or the pharmaceutically        acceptable salt thereof.    -   Embodiment 97. The method of any one of Embodiments 92-96,        wherein 1 ml of the suspension contains about 2 mg of        omeprazole, or the pharmaceutically acceptable salt thereof.    -   Embodiment 98. The method of any one of Embodiments 92-96,        wherein 1 ml of the suspension contains about 4 mg of        omeprazole, or the pharmaceutically acceptable salt thereof.    -   Embodiment 99. A method of preparing an oral pharmaceutical        suspension, comprising combining a first mixture comprising (a)        a therapeutically effective amount of omeprazole, or a        pharmaceutically acceptable salt thereof, wherein the first        mixture contains a percentage of moisture of no more than about        2.5%; with a second mixture comprising a second buffering agent,        wherein the second mixture contains a percentage of moisture of        no more than about 2.5%; to obtain a combined mixture, wherein        the combined mixture contains no sodium from a sodium-containing        buffering agent or the combined mixture contains sodium and        potassium at a ratio of from about 1:2.6 to about 1:3.4 by        weight; and adding water to the combined mixture.    -   Embodiment 100. The method of Embodiment 99, wherein the sodium        and potassium are present at a ratio of about 1:3.2 by weight.    -   Embodiment 101. The method of Embodiment 99 or 100, wherein the        first mixture has a moisture content of about 0.5% to about        1.5%.    -   Embodiment 102. The method of any one of Embodiments 99-101,        wherein the first mixture further comprises (b) a first        desiccant and/or the second mixture further comprises a second        desiccant.    -   Embodiment 103. The method of any one of Embodiments 99-102,        wherein the first desiccant and the second desiccant are sodium        alginate.    -   Embodiment 104. The method of any one of Embodiments 99-103,        wherein the first mixture further comprises (c) a first        buffering agent.    -   Embodiment 105. The method of any one of Embodiments 99-104,        wherein the first mixture and the second mixture are each        independently in a form of a powder, a pellet, a granule, a        seed, a bead, a spheroid, a microsphere, or a mixture thereof.    -   Embodiment 106. The method of any one of Embodiments 99-105,        wherein the omeprazole, or the pharmaceutically acceptable salt        thereof, is micronized.    -   Embodiment 107. The method of any one of Embodiments 99-105,        wherein the omeprazole, or the pharmaceutically acceptable salt        thereof, is a mixture of micronized and non-micronized        omeprazole, or the pharmaceutically acceptable salt thereof.    -   Embodiment 108. The method of Embodiment 107, wherein the        omeprazole comprises about 30 to about 70% micronized        omeprazole, or the pharmaceutically acceptable salt thereof, and        the rest of the omeprazole, or the pharmaceutically acceptable        salt thereof, is non-micronized.    -   Embodiment 109. The method of Embodiment 107, wherein the        omeprazole is a 1:1 mixture, by weight, of micronized and        non-micronized omeprazole, or the pharmaceutically acceptable        salt thereof.    -   Embodiment 110. The method of any one of Embodiments 99-109,        wherein the first buffering agent and the second buffering agent        are present in an amount sufficient to increase gastric fluid pH        to a pH that prevents degradation of at least some of the        omeprazole in the gastric fluid.    -   Embodiment 111. The method of any one of Embodiments 104-110,        wherein the first buffering agent and the second buffering agent        together provide a buffering capacity of about 2 mEq/ml dose of        the suspension.    -   Embodiment 112. The method of any one of Embodiments 99-111,        wherein the first buffering agent and the second buffering agent        are each independently selected from the group consisting of        alkali metal or alkaline earth metal carbonates, bicarbonates,        phosphates, citrates, borates, acetates, phthalates, tartrates,        and succinates.    -   Embodiment 113. The method of any one of Embodiments 99-112,        wherein the first buffering agent and the second buffering agent        are each independently selected from the group consisting of        sodium bicarbonate, potassium bicarbonate, and a mixture thereof    -   Embodiment 114. The method of any one of Embodiments 104-113,        wherein the first buffering agent is sodium bicarbonate.    -   Embodiment 115. The method of any one of Embodiments 99-113,        wherein the second buffering agent is a mixture of sodium        bicarbonate and potassium bicarbonate.    -   Embodiment 116. The method of Embodiment 115, wherein the        mixture comprises about 11% sodium bicarbonate and about 89%        potassium bicarbonate, by weight.    -   Embodiment 117. The method of any one of Embodiments 99-116,        wherein the first mixture and the second mixture together        comprise sodium bicarbonate and potassium bicarbonate at a ratio        of about 1:2.7 by weight.    -   Embodiment 118. The method of any one of Embodiments 99 and        101-113, wherein the first buffering agent and the second        buffering agent are potassium bicarbonate.    -   Embodiment 119. The method of any one of Embodiments 99-118,        wherein the second mixture further comprises a sweetener and a        preservative.    -   Embodiment 120. The method of any one of Embodiments 99-119,        wherein the oral pharmaceutical suspension is provided in a drug        delivery device suitable for multi-dose administration of        omeprazole.    -   Embodiment 121. A method of inhibiting gastric acid secretion,        comprising administering to a subject in need thereof an        effective amount of an oral pharmaceutical suspension comprising        water, a pharmaceutically effective amount of omeprazole, or a        pharmaceutically acceptable salt thereof, dispersed in the        water, and one or more buffering agents, wherein the suspension        contains no sodium from a sodium-containing buffering agent or        the suspension contains sodium and potassium at a ratio of from        about 1:2.6 to about 1:3.4 by weight; and wherein the oral        pharmaceutical suspension is prepared as claimed in any one of        Embodiments 99-120.    -   Embodiment 122. The oral pharmaceutical suspension of any one of        Embodiments 71-90, wherein the suspension remains stable for at        least one month at 2° C.-8° C. after constitution with water.

The disclosure also provides the following particular embodiments:

-   -   Embodiment I. A storage-stable omeprazole system, the system        comprising a therapeutically effective amount of omeprazole, or        a pharmaceutically acceptable salt thereof, wherein the system        contains a percentage of moisture of no more than about 2.5%,        and wherein the system contains no sodium from a        sodium-containing buffering agent or the system contains sodium        and potassium at a ratio of from about 1:2.6 to about 1:3.4 by        weight, and further wherein the storage-stable omeprazole system        is constituted with water prior to administration.    -   Embodiment II. The storage-stable omeprazole system of        Embodiment I, wherein the system comprises one or more buffering        agents each independently selected from the group consisting of        alkali metal or alkaline earth metal carbonates, bicarbonates,        phosphates, citrates, borates, acetates, phthalates, tartrates,        and succinates.    -   Embodiment III. The storage-stable omeprazole system of        Embodiment I, the system comprising (i) a first mixture        comprising (a) a therapeutically effective amount of omeprazole,        or a pharmaceutically acceptable salt thereof, wherein the first        mixture contains a percentage of moisture of no more than about        2.5%; and (ii) a second mixture comprising a second buffering        agent, wherein the second mixture contains a percentage of        moisture of no more than about 2.5%, wherein the first mixture        and the second mixture are stored separately from each other and        are mixed together on or just before constitution with water,        and wherein the system contains no sodium from a        sodium-containing buffering agent or the system contains sodium        and potassium at a ratio of from about 1:2.6 to about 1:3.4 by        weight.    -   Embodiment IV. A storage-stable omeprazole powder system, the        system comprising (i) a first powder mixture comprising (a) a        therapeutically effective amount of omeprazole, or a        pharmaceutically acceptable salt thereof, (b) sodium alginate,        and (c) a first buffering agent; and (ii) a second powder        mixture comprising sodium alginate and a second buffering agent,        wherein the first powder mixture and the second powder mixture        are stored separately from each other and are mixed together on        or just before constitution with water, and wherein the system        contains sodium and potassium at a ratio of from about 1:2.6 to        about 1:3.4 by weight.    -   Embodiment V. The storage-stable omeprazole system or the        storage-stable omeprazole powder system of any one of        Embodiments I-IV, wherein the omeprazole or the pharmaceutically        acceptable salt thereof is micronized.    -   Embodiment VI. The storage-stable omeprazole system or the        storage-stable omeprazole powder system of any one of        Embodiments I-IV, wherein the omeprazole or the pharmaceutically        acceptable salt thereof is a mixture of micronized and        non-micronized omeprazole or the pharmaceutically acceptable        salt thereof.    -   Embodiment VII. The storage-stable omeprazole system or the        storage-stable omeprazole powder system of any of the preceding        claims, wherein the storage-stable omeprazole system or the        omeprazole powder system is provided in a drug delivery device        suitable for multi-dose administration of omeprazole, or the        pharmaceutically acceptable salt thereof    -   Embodiment VIII. The storage-stable omeprazole powder system of        Embodiment IV or VII, wherein the storage-stable omeprazole        powder system is provided in a container body comprising a cap,        wherein (i) the container body contains the second powder        mixture and has a container opening formed in an upper end        thereof; (ii) the cap comprises a cylindrical accommodation        portion comprising the first powder mixture and a cap portion        sealing an upper end of the accommodation portion, and        wherein (iii) the cap is mounted in the container opening of the        container body, wherein when the cap is twisted, the first        powder mixture is released into the container body.    -   Embodiment IX. The storage-stable omeprazole system or the        storage-stable omeprazole powder system of any one of the        preceding claims, wherein the omeprazole system or the        omeprazole powder system remains stable at 25° C./60% relative        humidity for at least 2 years.    -   Embodiment X. An oral pharmaceutical suspension, comprising        water, a pharmaceutically effective amount of omeprazole, or a        pharmaceutically acceptable salt thereof, dispersed in the        water, and one or more buffering agents, and wherein the        suspension contains no sodium from a sodium-containing buffering        agent or the suspension contains sodium and potassium at a ratio        of from about 1:2.6 to about 1:3.4 by weight.    -   Embodiment XI. The oral pharmaceutical suspension of Embodiment        X, wherein about 1 ml of the suspension contains from about 1 mg        to about 10 mg of omeprazole, or the pharmaceutically acceptable        salt thereof.    -   Embodiment XII. The oral pharmaceutical suspension of Embodiment        X or XI, wherein the suspension remains stable for at least one        month at 2° C.-8° C. after constitution with water.    -   Embodiment XIII. A method of inhibiting gastric acid secretion,        comprising administering to a subject in need thereof an        effective amount of the oral pharmaceutical suspension of any        one of Embodiments X-XII.    -   Embodiment XIV. A method of administering an oral pharmaceutical        suspension to a subject in need of inhibition of gastric acid        secretion, said method comprising 1) preparing an oral        pharmaceutical suspension, comprising combining a first mixture        comprising a therapeutically effective amount of omeprazole, or        a pharmaceutically acceptable salt thereof, wherein the first        mixture contains a percentage of moisture of no more than about        2.5%; with a second mixture comprising a second buffering agent,        wherein the second mixture contains a percentage of moisture of        no more than about 2.5%; to obtain a combined mixture, wherein        the combined mixture contains no sodium from a sodium-containing        buffering agent or the combined mixture contains sodium and        potassium at a ratio of from about 1:2.6 to about 1:3.4 by        weight; and adding water to the combined mixture; and 2)        administering to the subject in need thereof an effective amount        of the oral pharmaceutical suspension.    -   Embodiment XV. The method of Embodiment XIII or XIV, wherein the        subject is a child.

EXAMPLES

The formulations described herein is now further detailed with referenceto the following examples. These examples are provided for the purposeof illustration only and the embodiments described herein should in noway be construed as being limited to these examples. Rather, theembodiments should be construed to encompass any and all variationswhich become evident as a result of the teaching provided herein.

Example 1 Exemplary Formulation and Manufacturing Details of Omeprazole2 mg/ml and 4 mg/ml Oral Suspensions and Storage-Stable OmeprazolePowder Systems

In the Table 1 below, the granulate composition is used in thepreparation of an example of the first mixture present in thestorage-stable omeprazole powder systems described herein.

TABLE 1 Omeprazole Oral Susp'n Constituted Susp'n Example A Example BExample C Composition mg/ml mg/ml mg/ml Omeprazole 2 4 4 SodiumBicarbonate 51.2 51.2 51.2 Potassium Bicarbonate 139 139 139 SodiumAlginate 1.17 1.17 1.17 Mannitol 4.99 5.00 4.99 Sucralose 3.99 3.99 3.99Sodium Alginate (Dried) 23.8 23.8 23.8 Xanthan Gum 2.86 2.85 2.86Vanilla Flavour (Powder) 10.00 5.01 10.00 Sodium Benzoate 5.00 5.01 5.00Methylparaben Sodium 2.29 2.29 2.29 Maltitol Powder 272 280 272 TitaniumDioxide 3.89 3.90 3.89 Water QS 1 ml QS 1 ml QS 1 ml GranulateComposition mg/g mg/g mg/g Omeprazole 53.73 101.98 101.98 SodiumBicarbonate 914.93 868.27 868.27 Sodium Alginate 31.34 29.75 29.75Granulate Batch Size (Kg) 13.400 14.120 14.120 Granulation EquipmentYenchen YC-MGB-50/25 Super Mixer/Granulator/50 L Bowl/Yenchen YC-CM-1Conemill, 0.6 mm screen Granulation Solvent Water Water WaterSolvent:Solids Ratio (L:Kg) 0.09 0.11 0.11 Drying Equipment YenchenYC-FBD-15 Fluid Bed Dryer Drying Temperature (° C.) 40 40 40 MillingEquipment Yenchen YC-CM-1-Conemill Blend Lot No 17F03 RD17-017 17F06First mixture Composition mg/g mg/g mg/g Milled Granulate 881.54 887.43887.00 Mannitol 7.90 7.54 7.54 Sodium Alginate (Dried) 110.55 105.26105.45 Blend Size (Kg) 9.100 1.368 9.540 Blending Equipment PharmatechMB Yenchen V-Mixer Pharmatech MB 400/50 L Drum 5 L Drum 400/50 L DrumBlending Conditions 25 rpm/30 mins 40 rpm/45 mins 25 rpm/30 mins CapsLot No 17F03 RD 17-017 17F06 Cap Filling/Sealing MCPI Fine DosingOpti-feeder/i-DOSiTECNO Table Top Capping Machine Equipment Target FillWeight (g) 3.800 3.980 3.980 Mean In Process Fill 3.794 3.997 3.979Weight (g) Actual In Process Fill 98.47%-100.79% 100.03%-101.08%98.94%-101.58% Weight Range Target Fill Weight Target Fill Weight TargetFill Weight Second mixture Batch Size 43.000 20.000 43.000 (Kg) Secondmixture Composition mg/g mg/g mg/g Sodium Bicarbonate 35.67 35.40 35.67Potassium Bicarbonate 290.24 288.05 290.24 Mannitol 9.71 9.65 9.71Sucralose 8.32 8.25 8.32 Sodium Alginate (Dried) 39.83 39.65 39.83Xanthan Gum 5.97 5.90 5.97 Vanilla Flavour (Powder) 20.84 10.35 20.84Sodium Benzoate 10.42 10.35 10.42 Methylparaben Sodium 4.77 4.73 4.77Maltitol Powder 566.15 579.70 566.15 Titanium Dioxide 8.11 8.05 8.11Second mixture Sub Lot 23.801 23.801 N/A 23.801 23.801 Batch Size (Kg)Second mixture Sub Lot Yenchen YC Yenchen YC N/A Yenchen YC Yenchen YCManufacturing Equipment MGB-50/25 MGB-50/25 MGB-50/25 MGB-50/25 SuperMixer/ Super Mixer/ Super Mixer/ Super Mixer/ Granulator 50 L Granulator50 L Granulator 50 L Granulator 50 L Second mixture Sub Lot High speedHigh speed N/A High speed High speed Blending impellor & impellor &impellor & impellor & Conditions chopper for 10 chopper for 10 chopperfor 10 chopper for 10 mins pre flavour/ mins pre flavour/ mins preflavour/ mins pre flavor/ low speed low speed low speed low speedimpellor for 3 impellor for 3 impellor for 3 impellor for 3 mins postflavour mins post flavour mins post flavour mins post flavour Secondmixture Pharmatech MB 400 Yenchen YC MGB- Pharmatech MB 400Manufacturing (100 L Blender Drum) 50/25 Super (100 L Blender Drum)Equipment Mixer/Granulator 50 L Second mixture Blending 25 rpm/10 minsHigh speed 25 rpm/10 mins Conditions impellor & chopper for 10 minsBottle Filling and Capping All-Fill Gravimetric Filling N/A-ManualAll-Fill Gravimetric Filling Equipment Machine/Flexicon Filling SystemMachine/Flexicon Filling System Target Fill Weight (g) 43.19 43.54743.19 Mean In Process Fill 43.075 43.679 43.047 Weight (g) Actual InProcess Fill 98.16%-101.01% 98.98%-101.04% 98.84%-100.23% Weight RangeTarget Fill Weight Target Fill Weight Target Fill Weight

Example 2

-   -   Exemplary Formulations of Omeprazole 2 mg/ml and 4 mg/ml Oral        Suspensions

TABLE 2 Omeprazole Oral Susp'n 2 2 2 4 4 4 Strength (mg/ml) OmeprazoleOral Example D Example E Example F Example G Example H Example ISuspension Example Constituted mg/ml mg/ml mg/ml mg/ml mg/ml mg/mlSuspension Composition Omeprazole 2 2 2 4 4 4 Sodium Bicarbonate 51.251.2 51.2 51.2 51.2 51.2 Potassium Bicarbonate 139 139 139 139 139 139Sodium Alginate 25.0 25.0 25.0 25.0 25.0 25.0 Mannitol 5.00 5.00 5.005.00 5.00 5.00 Sucralose 4.00 4.00 4.00 4.00 4.00 4.00 Xanthan Gum 2.862.86 2.86 2.86 2.86 2.86 Mint Flavour (Powder) 2.50 2.50 2.50 5.00 5.005.00 Vanilla Flavour (Powder) 10.0 10.0 10.0 N/A N/A N/A Sodium Benzoate5.00 5.00 5.00 5.00 5.00 5.00 Methyl Paraben Sodium 2.29 2.29 2.29 2.292.29 2.29 Maltitol Powder 272 272 272 272 272 272 Titanium Dioxide 3.903.90 3.90 3.90 3.90 3.90 Water qs 1 ml qs 1 ml qs 1 ml qs 1 ml qs 1 mlqs 1 ml Buffering Capacity 2 2 2 2 2 2 (mEq/ml)

Example 3

-   -   Exemplary Chemical Composition of an Omeprazole Oral Suspension

TABLE 3 Compound mg/ml omeprazole 4 Buffering Agents: Sodium hydrogen51.2 carbonate (sodium bicarbonate) Potassium hydrogen 139 carbonate(potassium bicarbonate) Granulating agent/internaldesiccant/stabilizer/thickener: Sodium alginate 25.0 Sweeteners:Maltitol 272 Mannitol 5.00 Sucralose 4.00 Viscosity modifier: Xanthangum 2.86 Flavors: Mint 5.00 Opacifier: Titanium oxide 3.90 Preservativesystem: Sodium benzoate 5.00 Sodium methylparaben 2.29 Bufferingcapacity 2 mEq/ml

Example 4

This example demonstrates the benefit of the storage-stable omeprazolepowder systems of the disclosure on the stability of constitutedomeprazole oral suspensions according to the present disclosure.

Omeprazole 2 mg/ml oral suspensions of Example J, Example K, and ExampleL were prepared having identical constituted suspension compositions,but they included the following differences:

Example J is an aluminium (Alu) foil packaged two chamber dosage formaccording to the present disclosure comprising a cap containing a firstpowder mixture fastened on a bottle containing a second powder mixture;

Example K is a comparative example of an Alu foil packaged two chamberdosage form comprising a cap containing a first powder mixture fastenedon a bottle containing a second powder mixture which had beenconstituted with water; and

Example L is a comparative example of an Alu foil packaged singlechamber dosage form comprising a capped bottle containing a powdermixture of a first powder mixture and a second powder mixture.

A description of the manufacturing, packaging and constitution detailsfor the prepared omeprazole 2 mg/ml suspensions of Examples J, K, and Lis provided below:

Drying of Sodium Alginate (Batch Size: 3.600 Kg) 1. Sodium alginate wasdried in a VD53 Binder Vacuum Drying Oven (i) under a vacuum ofapproximately 600 mbar and a temperature setting of approximately 85° C.until a loss on drying specification of NMT 3% was met and then (ii)under a vacuum of <100 mbar and a temperature setting of approximately85° C. until a loss on drying specification of NMT 2% was met.Manufacture of Omeprazole Granulate (Batch Size: 13.400 Kg) 2. Sodiumhydrogen carbonate, micronised omeprazole and sodium alginate wereadded, via a 2 mm screen, to the Yenchen Super Mixer/Granulator YC-MGB-50/25 (50 L bowl), and mixed for approximately 15 minutes at highimpellor speed and high chopper speed. 3. 1250 ml purified water wasadded to the sodium hydrogen carbonate, micronised omeprazole and sodiumalginate dry mixture in the Yenchen Super Mixer/ Granulator YC-MGB-50/25over approximately 5 minutes, while mixing at low impellor speed andhigh chopper speed. Mixing was continued for approximately 1 furtherminute at low impellor speed and high chopper speed after which themixture was mixed for approximately 1 minute at high impellor speed andhigh chopper speed. 4. The wet granulate was screened through a 2 mmscreen using a Yenchen YC-CM-1 Cone Mill at approximately 600 rpm. 5.The screened wet granulate was loaded into a Yenchen YC-FBD-15 Fluid BedDryer and the granules were dried at a temperature setting ofapproximately 40° C. until the loss of drying specification of NMT 1.5%was met. 6. The resulting dry granulate was milled initially through a0.8 mm screen, and then through a 0.6 mm screen, using a Yenchen YC-CM-1Cone Mill at approximately 450 rpm. Manufacture of First Powder Mixture(Batch Size: 9.100 Kg) 7. The milled dry granulate, mannitol (via a 0.8mm screen) and dried sodium alginate (via a 0.8 mm screen) were loadedinto a Pharmatech Multiblend Blender MB 400 (50 L drum) and blended forapproximately 30 minutes at approximately 25 rpm. PICS Cap Manufacture(Batch Size: 2394 caps) 8. The first powder mixture was filled intopolypropylene PICS Caps to a target fill weight of 3.80 g on a MCPI FineDosing Optifeeder. The head space above the powder fill in the PICS Capswas partially evacuated under vacuum and then flushed with nitrogenbefore sealing the PICS Caps with the seal disks using the i-DOSiTECHNOTable Top Capping Machine. Second Powder Mixture Manufacture [23.929 Kg]9. Potassium hydrogen carbonate was milled initially through a 2 mmscreen, and then through a 0.6 mm screen, at approximately 450 rpm usinga Yenchen YC-CM-1 Cone Mill. 10. Sodium methyl parahydroxybenzoate wasscreened through a 0.8 mm mesh hand screen. 11. Maltitol, milledpotassium hydrogen carbonate, dried sodium alginate, sodium hydrogencarbonate, sodium benzoate, mannitol, sucralose, titanium dioxide,xanthan gum and screened sodium methyl parahydroxybenzoate were screenedthrough a 2 mm mesh hand screen into a Yenchen Super Mixer/GranulatorYC- MGB-50/25 (50 L Bowl) and blended for approximately 10 minutes athigh impellor speed and high chopper speed. The mint and vanillaflavours, via a 2 mm mesh hand screen, were added to the resultingmixture in the Yenchen Super Mixer/Granulator YC-MGB-50/25 and blendedfor approximately 3 minutes at low impellor speed. Bottle Filling andCapping [Batch Size: 200 Bottles] 12. The final second powder mixturewas filled into 150 ml amber PET bottles to a target fill weight of43.40 g using an All Fill Series 10 Gravimetric Filling Machine and thebottles were capped with the first powder mixture filled PICS Caps usinga Flexicon FF30 Table Top Capping equipment. Further Processingincluding Packaging 13. Example J-Alu Foil Packaged Two Chamber DosageForm Comprising PICS Cap Containing First Powder Mixture Fastened onBottle Containing Second Powder Mixture. The filled and capped bottlesfrom Step 12 were packaged by placing the bottle in an Alu Foil Pouchand sealing the open end of the Alu Foil Pouch using a Hawo hpl WSZ HandSealer (temperature setting 150° C., holding time one to two seconds).Example K-Alu Foil Packaged Two Chamber Dosage Form Comprising PICS CapContaining First Powder Mixture Fastened on Bottle Containing SecondPowder Mixture which had been Constituted with Water. The second powdermixture contents of the bottle for the filled and capped bottles fromStep 12 was constituted as follows: The powder was loosened by shaking/agitating the bottle vigorously for 20 seconds. The base of the bottlewas tapped three times on a hard horizontal surface. The first powdermixture filled PICS Cap was removed from the bottle. 64 ml of water wasadded to the second powder mixture content of the bottle. The firstpowder mixture filled PICS Cap was securely refastened onto the bottle.The bottle was shaken vigorously for 30 seconds. The resulting cappedbottles were packaged by placing the capped bottle in an Alu Foil Pouchand sealing the open end of the Alu Foil Pouch using a Hawo hpl WSZ HandSealer (temperature setting 150° C., holding time one to two seconds).The alu foil packaged bottles were loaded upright in a cardboard box.Example L-Alu Foil Packaged Single Chamber Dosage Form Comprising aCapped Bottle Containing a Powder Mixture of First Powder Mixture andSecond Powder Mixture The contents of the PICS Cap and the contents ofthe bottle for the filled and capped bottles from Step 12 were mixed asfollows: The powder was loosened by shaking/agitating the bottle for 10seconds. The powder in the red PICS cap was released into the bottle bytwisting the red cap anti-clockwise until the seal was broken. The redcap was twisted back to the original position, securely fastening thered cap onto the bottle. While holding the bottle upright, the powderwas swirled for ten seconds. The bottle was shaken vigorously for afurther 10 seconds. The base of the bottle was tapped three times on ahard horizontal surface. The resulting capped and bottled mixture waspackaged by placing the bottle in an Alu Foil Pouch and sealing the openend of the Alu Foil Pouch using a Hawo hpl WSZ Hand Sealer (temperaturesetting 150° C. , holding time one to two seconds). FollowedConstitution Instructions Example J Shake the bottle for 10 seconds toloosen the powder. Twist the red cap anti- clockwise until the seal isbroken to release the powder in the red cap into the bottle. Twist thered cap back to the original position, securely fastening the red caponto the bottle. Shake the bottle vigorously for ten seconds. Tap thebase of the bottle three times on a hard horizontal surface. Remove thered cap from the bottle. Add 64 mL of water by using a suitablemeasuring device. Securely fasten the red cap onto the bottle and shakevigorously for 30 seconds. Remove the red cap and red ring and throwaway. Insert the Bottle Adaptor and replace the red cap with the greyplastic screw-cap. Leave for fifteen minutes. Shake for 20 seconds priorto each use. Example K Shake the bottle for 10 seconds to loosen thepowder. Twist the red cap anti- clockwise until the seal is broken torelease the powder in the red cap into the bottle. Twist the red capback to the original position, securely fastening the red cap onto thebottle. Tap the base of the bottle three times on a hard horizontalsurface. Securely fasten the red cap onto the bottle and shakevigorously for 30 seconds. Remove the red cap and red ring and throwaway. Insert the Bottle Adaptor and replace the red cap with the greyplastic screw-cap. Leave for fifteen minutes. Shake for 20 seconds priorto each use. Example L Shake the bottle for 10 seconds to loosen thepowder. Tap the base of the bottle three times on a hard horizontalsurface. Remove the red cap from the bottle. Add 64 mL of water by usinga suitable measuring device. Securely fasten the red cap onto the bottleand shake vigorously for 30 seconds. Remove the red cap and red ring andthrow away. Insert the Bottle Adaptor and replace the red cap with thegrey plastic screw-cap. Leave for fifteen minutes. Shake for 20 secondsprior to each use.

A summary of the formulation and characterization details of theomeprazole 2 mg/ml oral suspensions of Example J, Example K, and ExampleL is provided in Table 4.

TABLE 4 OMEPRAZOLE 2 MG/ML SUSPENSIONS Example J Example K Example LDESCRIPTION Alu Foil Packaged Two Alu Foil Packaged Two Alu FoilPackaged OF DOSAGE Chamber Dosage Form Chamber Dosage Form SingleChamber FORM BEFORE Comprising Cap Comprising Cap Dosage FormCONSTITUTION Containing First Powder Containing First Powder Comprisinga Capped OF FINISHED Mixture Fastened on Mixture Fastened on BottleContaining a PRODUCT Bottle Containing Bottle Containing Powder Mixtureof First Second Powder Mixture Second Powder Mixture Powder Mixture andwhich had been Second Powder Mixture Constituted with Water FIRST POWDERMIXTURE COMPONENT Average LOD of Omeprazole 0.52% 0.52% 0.52% GranulateOmeprazole Granulate Composition mg/g mg/g mg/g Omeprazole 53.73 53.7353.73 Sodium Bicarbonate 914.93 914.93 914.93 Sodium Alginate 31.3431.34 31.34 Average LOD of Dried Alginate 1.05% 1.05% 1.05% First PowderMixture Composition mg/g mg/g mg/g Milled Omeprazole Granulate 881.58881.58 881.58 Mannitol 7.90 7.90 7.90 Sodium Alginate (Dried) 110.52110.52 110.52 Average LOD of First 0.70% 0.70% 0.70% Powder MixtureSECOND POWDER MIXTURE COMPONENT Average LOD of Dried Alginate 0.79%0.79% 0.79% mg/g Second Powder Mixture (before addition Composition mg/gof 64 ml water) mg/g Sodium Bicarbonate 35.46 35.46 35.46 PotassiumBicarbonate 288.72 288.72 288.72 Mannitol 9.67 9.67 9.67 Sucralose 8.308.30 8.30 Sodium Alginate (Dried) 39.60 39.60 39.60 Xanthan Gum 5.935.93 5.93 Mint Flavour 5.19 5.19 5.19 Vanilla Flavour 20.74 20.74 20.74Sodium Benzoate 10.37 10.37 10.37 Methylparaben Sodium 4.74 4.74 4.74Maltitol Powder 563.20 563.20 563.20 Titanium Dioxide 8.08 8.08 8.08Average LOD of Second  0.6%  0.6%  0.6% Powder Mixture CONSTITUTEDFINISHED PRODUCT Constituted Suspension Composition mg/ml mg/ml mg/mlOmeprazole 2 2 2 Sodium Bicarbonate 51.2 51.2 51.2 Potassium Bicarbonate139 139 139 Sodium Alginate 1.17 1.17 1.17 Mannitol 5.00 5.00 5.00Sucralose 4.00 4.00 4.00 Sodium Alginate (Dried) 23.8 23.8 23.8 XanthanGum 2.86 2.86 2.86 Mint Flavour 2.50 2.50 2.50 Vanilla Flavour 10.0010.00 10.00 Sodium Benzoate 5.00 5.00 5.00 Methylparaben Sodium 2.292.29 2.29 Maltitol Powder 272 272 272 Titanium Dioxide 3.90 3.90 3.90Water qs 1 ml qs 1 ml qs 1 ml Sodium Content of Finished 86 mg/5 ml 86mg/5 ml 86 mg/5 ml Product Sodium:Potassium in Finished 1:3.2 1:3.21:3.2 Product Sodium Bicarbonate:Potassium 1:2.7 1:2.7 1:2.7 Bicarbonatein Finished Product Buffering Capacity of Finished 2 mEq/ml 2 mEq/ml 2mEq/ml Product

A summary of the results of the stability study on the omeprazole 2mg/ml oral suspensions of Example J, Example K, and Example L isprovided in Table 5.

TABLE 5 OMEPRAZOLE 2 MG/ML SUSPENSION Example J Example K Example LDESCRIPTION Alu Foil Packaged Two Alu Foil Packaged Two Alu FoilPackaged OF DOSAGE Chamber Dosage Form Chamber Dosage Form SingleChamber FORM BEFORE Comprising Cap Comprising Cap Dosage FormCONSTITUTION Containing First Powder Containing First Powder Comprisinga Capped OF FINISHED Mixture Fastened on Mixture Fastened on BottleContaining a PRODUCT Bottle Containing Bottle Containing Powder Mixtureof First Second Powder Mixture Second Powder Mixture Powder Mixture andwhich had been Second Powder Mixture Constituted with Water STABILITYStability Storage 40° C./75% RH 40° C./75% RH 40° C./75% RH Conditionsfor 3 months for 3 months for 3 months (Alu Foil Packaged (Alu FoilPackaged (Alu Foil Packaged Product) then 2 Product) then 2 Product)then 2 months at 2° C.- months at 2° C.- months at 2° C.- 8° C.(Constituted 8° C. (Constituted 8° C. (Constituted Finished Product)Finished Product) Finished Product) Constituted Product on Day ofConstitution Total Impurities  0.11% 1.49% 7.59% Sodium Benzoate Content100.5% 98.3% Not Tested Sodium Methyl  95.9% 10.1% Not TestedParahydroxybenzoate Content pH 8.1 8.3 8.1 Buffer Capacity 2.0 mEq/ml2.0 mEq/ml 2.1 mEq/ml Constituted Product after 28 days at 2°-8° C.Total Impurities  0.23% 2.19% 6.79% Sodium Benzoate Content    98% 96.6%Not Tested Sodium Methyl    94% 10.4% Not Tested ParahydroxybenzoateContent pH 8.3 8.5 8.3 Buffer Capacity 2.0 mEq/ml 2.0 mEq/ml 2.1 mEq/mlConstituted Product after 56 days at 2°-8° C. Total Impurities  0.33%4.41% 11.02%  Sodium Benzoate Content  93.4% 95.8% Not Tested SodiumMethyl  86.1% 10.3% Not Tested Parahydroxybenzoate Content pH 8.1 8.38.3 Buffer Capacity 2.1 mEq/ml 2.0 mEq/ml 2.0 mEq/ml

Example 5 An Exemplary Chemical Composition of an Omeprazole OralSuspension Prepared Using Micronized Omeprazole

A description of the manufacturing, packaging and constitution detailsfor the prepared omeprazole 4 mg/ml suspension of Example M is providedbelow:

Drying of Sodium Alginate (Batch Size: 3.600 Kg) 1. Sodium alginate wasdried in a VD53 Binder Vacuum Drying Oven (i) under a vacuum ofapproximately 600 mbar and a temperature setting of approximately 85° C.until a loss on drying specification of NMT 3% was met and then (ii)under a vacuum of <100 mbar and a temperature setting of approximately85° C. until a loss on drying specification of NMT 2% was metManufacture of Omeprazole Granulate (Batch Size: 14.120 Kg) 2. Sodiumhydrogen carbonate, micronised omeprazole and sodium alginate wereadded, via a 2 mm screen, to the Yenchen Super Mixer/Granulator YC-MGB-50/25 (50 L bowl), and mixed for approximately 15 minutes at highimpellor speed and high chopper speed. 3. 1550 ml purified water wasadded to the sodium hydrogen carbonate, micronised omeprazole and sodiumalginate dry mixture in the Yenchen Super Mixer/ Granulator YC-MGB-50/25over approximately 5 minutes, while mixing at low impellor speed andhigh chopper speed. The mixture was mixed for approximately 1 furtherminute at low impellor speed and high chopper speed after which it wasmixed for approximately 1 minute at high impellor speed and high chopperspeed. 4. The wet granulate was screened through a 2 mm screen using aYenchen YC-CM-1 Cone Mill at approximately 600 rpm. 5. The screened wetgranulate was loaded into a Yenchen YC-FBD-15 Fluid Bed Dryer and thegranules were dried at a temperature setting of approximately 40° C.until the loss of drying specification of NMT 1.5% was met. 6. Theresulting dry granulate was milled initially through a 0.8 mm screen,and then through a 0.6 mm screen, using a Yenchen YC-CM-1 Cone Mill atapproximately 450 rpm. Manufacture of First Powder Mixture (Batch Size:9.540 Kg) 7. The milled dry granulate, mannitol (via a 0.8 mm screen)and dried sodium alginate (via a 0.8 mm screen) were loaded into aPharmatech Multiblend Blender MB 400 (50 L drum) and blended forapproximately 30 minutes at approximately 25 rpm. PICS Cap Manufacture(Batch Size: 2396 caps) 8. The first powder mixture was filled intopolypropylene PICS Caps to a target fill weight of 3.98 g on a MCPI FineDosing Optifeeder. The head space above the powder fill in the PICS Capswas partially evacuated under vacuum and then flushed with nitrogenbefore sealing the PICS Caps with the seal disks using an i-DOSiTECHNOTable Top Capping Machine. Second Powder Mixture Sub Lot Manufacture[23.500 Kg] 9. Potassium hydrogen carbonate was milled initially througha 2 mm screen, and then through a 0.6 mm screen, at approximately 450rpm using a Yenchen YC-CM-1 Cone Mill. 10. Sodium methylparahydroxybenzoate was screened through a 0.8 mm mesh hand screen. 11.Maltitol, milled potassium hydrogen carbonate, dried sodium alginate,sodium hydrogen carbonate, sodium benzoate, mannitol, sucralose,titanium dioxide, xanthan gum and screened sodium methylparahydroxybenzoate were screened through a 2 mm mesh hand screen into aYenchen Super Mixer/Granulator YC- MGB-50/25 (50 L Bowl) and blended forapproximately 10 minutes at high impellor speed and high chopper speed.The mint flavour was added via a 2 mm mesh hand screen, to the resultingmixture in the Yenchen Super Mixer/Granulator YC-MGB-50/25 and blendedfor approximately 3 minutes at low impellor speed. 12. Steps 9, 10 and11 were repeated for a further second powder mixture sublot. FinalSecond Powder Mixture Manufacture (45 Kg) 13. The two second powdermixture sub lots were added into a Pharmatech Multiblend Blender MB 400(100 L drum) and blended for approximately 10 minutes at approximately25 rpm Bottle Filling and Capping [Batch Size: 1052 Bottles] 14. Thefinal second powder mixture was filled into 150 ml amber PET bottles toa target fill weight of 42.75 g using an All Fill Series 10 GravimetricFilling Machine and the bottles were capped with the first powdermixture filled PICS Caps using a Flexicon FF30 Table Top Cappingequipment. Further Processing including Packaging 15. The filled andcapped bottles from Step 14 were packaged by placing the bottle in anAlu Foil Pouch and sealing the open end of the Alu Foil Pouch using aHawo hpl WSZ Hand Sealer (temperature setting 150° C., holding time oneto two seconds). Followed Constitution Instructions Example M Shake thebottle for 10 seconds to loosen the powder. Twist the red cap anti-clockwise until the seal is broken to release the powder in the red capinto the bottle. Twist the red cap back to the original position,securely fastening the red cap onto the bottle. Shake the bottlevigorously for ten seconds. Tap the base of the bottle three times on ahard horizontal surface. Remove the red cap from the bottle. Add 64 mLof water by using a suitable measuring device. Securely fasten the redcap onto the bottle and shake vigorously for 30 seconds. Remove the redcap and red ring and throw away. Insert the Bottle Adaptor and replacethe red cap with the grey plastic screw-cap. Leave for fifteen minutes.Shake for 20 seconds prior to each use.

A summary of the formulation and characterization details of theomeprazole 4 mg/ml oral suspension of Example M is provided in Table 6.

TABLE 6 OMEPRAZOLE 4 MG/ML SUSPENSION Example M DESCRIPTION OF Alu FoilPackaged Two DOSAGE Chamber Dosage Form FORM BEFORE Comprising CapContaining CONSTITUTION First Powder Mixture Fastened OF FINISHED onBottle Containing Second PRODUCT Powder Mixture FIRST POWDER MIXTURECOMPONENT Omeprazole Granulate Composition mg/g Omeprazole 101.98 SodiumBicarbonate 868.27 Sodium Alginate 29.75 Average LOD of Omeprazole 0.62%Granulate Average LOD of Dried Alginate 1.30% First Powder MixtureComposition mg/g Milled Omeprazole Granulate 886.96 Mannitol 7.54 SodiumAlginate (Dried) 105.50 Average LOD of First 0.83% Powder Mixture SECONDPOWDER MIXTURE COMPONENT Average LOD of Dried Alginate 1.30% SecondPowder Mixture Composition mg/g Sodium Bicarbonate 36.03 PotassiumBicarbonate 293.29 Mannitol 9.82 Sucralose 8.42 Sodium Alginate (Dried)40.36 Xanthan Gum 6.03 Mint Flavour 10.52 Sodium Benzoate 10.52Methylparaben Sodium 4.82 Maltitol Powder 571.99 Titanium Dioxide 8.20Average LOD of Final 0.50% Second Powder Mixture CONSTITUTED FINISHEDPRODUCT Constituted Suspension Composition mg/ml Omeprazole 4 SodiumBicarbonate 51.2 Potassium Bicarbonate 139 Sodium Alginate 1.17 Mannitol5.00 Sucralose 4.00 Sodium Alginate (Dried) 23.8 Xanthan Gum 2.86 MintFlavour 5.00 Sodium Benzoate 5.00 Methylparaben Sodium 2.29 MaltitolPowder 272 Titanium Dioxide 3.90 Water qs 1 ml Sodium Content of 86 mg/5ml Finished Product Sodium:Potassium in 1:3.2 Finished Product SodiumBicarbonate:Potassium Bicarbonate in Finished Product 1:2.7 BufferingCapacity 2 mEq/ml

A summary of the results of a stability study on the omeprazole 4 mg/mloral suspension of Example M is provided in Table 7.

TABLE 7 OMEPRAZOLE 4 MG/ML SUSPENSION Example M DESCRIPTION OF DOSAGEAlu Foil Packaged Two Chamber FORM BEFORE CONSTITUTION Dosage FormComprising Cap Containing OF FINISHED PRODUCT First Powder MixtureFastened on Bottle Containing Second Powder Mixture STABILITY StabilityStorage Conditions 25° C./60% RH for 24 months (Alu Foil PackagedProduct) T = 0 T = 6 months T = 12 months T = 18 month T = 24 monthsOmeprazole Content    97%  102%   99%  100%   99% LOD (Contents of PICSCap    0.8%  0.9%  0.9%  0.9%  0.7% Chamber) LOD (Contents of BottleChamber)    0.5%  0.8%  0.7%  0.7%  0.7% Total Impurities <0.05% 0.10%0.10% 0.10% 0.05% Sodium Benzoate Content    98%  100%   98%   99%   99%Sodium Methyl   100%   99%   99%  101%  100% Parahydroxybenzoate ContentpH 8.1 Not Tested 8.0 8.1 8.1

Example 6 Exemplary Chemical Compositions of Omeprazole Oral SuspensionsPrepared Using a Mixture of Micronized and Non-Micronized Omeprazole

A description of the manufacturing, packaging and constitution detailsfor the prepared omeprazole 4 mg/ml suspensions of Examples N and O isprovided below:

Drying of Sodium Alginate (Batch Size: 9.000 Kg) 1. Dry sodium alginatewas prepared in a Yenchen YC-FBD-15 Fluid Bed Dryer at a temperaturesetting of approximately 70° C. until the loss of drying specificationof no more than (NMT) 2.0% was met. Manufacture of Omeprazole Granulate(Batch Size: 14.120 Kg) 2. Sodium hydrogen carbonate, micronisedomeprazole, sieved (non-micronised) omeprazole and sodium alginate wereadded via a 2 mm screen, to a Yenchen Super Mixer/GranulatorYC-MGB-50/25 (50 L bowl), and mixed for approximately 15 minutes at highimpellor speed and high chopper speed. 3. 1500 ml of purified water wasadded to the sodium hydrogen carbonate, micronised omeprazole, sieved(non-micronised) omeprazole and sodium alginate dry mixture in theYenchen Super Mixer/Granulator YC-MGB-50/25 over approximately 5minutes, while mixing at low impellor speed and high chopper speed.Mixing was continued for approximately 1 further minute at low impellorspeed and high chopper speed after which the mixture was mixed forapproximately 1 minute at high impellor speed and high chopper speed. 4.The wet granulate was screened through a 2 mm screen using a YenchenYC-CM-1 Cone Mill at approximately 600 rpm. 5. The screened wetgranulate was loaded into a Yenchen YC-FBD-15 Fluid Bed Dryer and thegranules were dried at a temperature setting of approximately 40° C.until the loss of drying specification of NMT 1.5% was met. 6. Theresulting dry granulate was milled through a 0.6 mm screen, using aYenchen YC-CM-1 Cone Mill at approximately 450 rpm. Manufacture of FirstPowder Mixture (Batch Size: 10.903 Kg) 7. The milled dry granulate,mannitol (via a 0.8 mm screen) and dried sodium alginate (via a 0.8 mmscreen) were loaded into a Pharmatech Multiblend Blender MB 400 (50 Ldrum) and blended for approximately 30 minutes at approximately 25 rpm.PICS Cap Manufacture (Batch Size: 2739 caps) 8. The first powder mixturewas filled into polypropylene PICS Caps to a target fill weight of 3.98g on a MCPI Fine Dosing Optifeeder. The head space above the powder fillin the PICS Caps was partially evacuated under vacuum and then flushedwith nitrogen before sealing the PICS Caps with the seal disks using ani-DOSiTECHNO Table Top Capping Machine. Second Powder Mixture Sub LotManufacture [23.500 Kg] 9. Potassium hydrogen carbonate was milledinitially through a 2 mm screen, and then through a 0.6 mm screen, atapproximately 450 rpm using a Yenchen YC-CM-1 Cone Mill. 10. Sodiummethyl parahydroxybenzoate was screened through a 0.8 mm mesh handscreen. 11. Maltitol, milled potassium hydrogen carbonate, dried sodiumalginate, sodium hydrogen carbonate, sodium benzoate, mannitol,sucralose, titanium dioxide, xanthan gum and screened sodium methylparahydroxybenzoate were screened through a 2 mm mesh hand screen into aYenchen Super Mixer/Granulator YC- MGB-50/25 (50 L Bowl) and blended forapproximately 10 minutes at high impellor speed and high chopper speed.The mint flavour was added, via a 2 mm mesh hand screen, to theresulting mixture in the Yenchen Super Mixer/Granulator YC-MGB-50/25 andblended for approximately 3 minutes at low impellor speed. 12. Steps 9,10 and 11 were repeated for a further four second powder mixturesublots. Final Second Powder Mixture Manufacture (112.500 Kg) 13. Thefive second powder mixture sub lots were added into the PharmatechMultiblend Blender MB 400 (200 L drum) and blended for approximately 10minutes at approximately 25 rpm. Bottle Filling and Capping [Batch Size:1000 Bottles] 14. The final second powder mixture was filled into 150 mlamber PET bottles to a target fill weight of 42.75 g using an All FillSeries 10 Gravimetric Filling Machine and the bottles were capped withthe first powder mixture filled PICS Caps using a Flexicon FF30 TableTop Capping equipment. Further Processing including Packaging 15. Thefilled and capped bottles from Step 14 were packaged by placing thebottle in an Alu Foil Pouch and sealing the open end of the Alu FoilPouch using a Hawo hpl WSZ Hand Sealer (temperature setting 150° C.,holding time one to two seconds). Followed Constitution InstructionsExample N and Example O Shake the bottle for 10 seconds to loosen thepowder. Twist the red cap anti- clockwise until the seal is broken torelease the powder in the red cap into the bottle. Twist the red capback to the original position, securely fastening the red cap onto thebottle. Shake the bottle vigorously for ten seconds. Tap the base of thebottle three times on a hard horizontal surface. Remove the red cap fromthe bottle. Add 64 mL of water by using a suitable measuring device.Securely fasten the red cap onto the bottle and shake vigorously for 30seconds. Remove the red cap and red ring and throw away. Insert theBottle Adaptor and replace the red cap with the grey plastic screw-cap.Leave for fifteen minutes. Shake for 20 seconds prior to each use.

A summary of formulation and characterization details of the omeprazole4 mg/ml oral suspensions of Examples N and O is provided in Table 8.

TABLE 8 OMEPRAZOLE 4 MG/ML SUSPENSION Example N Example O DESCRIPTION OFAlu Foil Packaged Alu Foil Packaged DOSAGE Two Chamber Dosage TwoChamber Dosage FORM BEFORE Form Comprising Cap Form Comprising CapCONSTITUTION OF Containing First Powder Containing First Powder FINISHEDPRODUCT Mixture Fastened on Mixture Fastened on Bottle Containing BottleContaining Second Powder Mixture Second Powder Mixture FIRST POWDERMIXTURE COMPONENT Omeprazole Granulate Composition mg/g mg/g Omeprazole(micronized) 30.59 61.19 Omeprazole (sieved) 71.39 40.79 SodiumBicarbonate 868.27 868.27 Sodium Alginate 29.75 29.75 Average LOD ofOmeprazole  0.28%  0.38% Granulate Average LOD of Dried Alginate  0.79% 0.79% First Powder Mixture Composition mg/g mg/g Milled OmeprazoleGranulate 886.96 886.96 Mannitol 7.54 7.54 Sodium Alginate (Dried)105.50 105.50 Average LOD of First Powder  0.69%  0.59% Mixture SECONDPOWDER MIXTURE COMPONENT Average LOD of Dried Alginate  0.79%  0.79%Second Powder Mixture Composition mg/g mg/g Sodium Bicarbonate 36.0336.03 Potassium Bicarbonate 293.29 293.29 Mannitol 9.82 9.82 Sucralose8.42 8.42 Sodium Alginate (Dried) 40.36 40.36 Xanthan Gum 6.03 6.03 MintFlavour 10.52 10.52 Sodium Benzoate 10.52 10.52 Methylparaben Sodium4.82 4.82 Maltitol Powder 571.99 571.99 Titanium Dioxide 8.20 8.20Average LOD of Final Second  0.54%  0.54% Powder Mixture CONSTITUTEDFINISHED PRODUCT Constituted Suspension Composition mg/ml mg/mlOmeprazole 4 4 (30:70 micronised:sieved) (60:40 micronised:sieved)Sodium Bicarbonate 51.2 51.2 Potassium Bicarbonate 139 139 SodiumAlginate 1.17 1.17 Mannitol 5.00 5.00 Sucralose 4.00 4.00 SodiumAlginate (Dried) 23.8 23.8 Xanthan Gum 2.86 2.86 Mint Flavour 5.00 5.00Sodium Benzoate 5.00 5.00 Methylparaben Sodium 2.29 2.29 Maltitol Powder272 272 Titanium Dioxide 3.90 3.90 Water qs 1 ml qs 1 ml Sodium Contentof Finished 86 mg/5 ml 86 mg/5 ml Product Sodium:Potassium in 1:3.21:3.2 Finished Product Sodium Bicarbonate:Potassium 1:2.7 1:2.7Bicarbonate in Finished Product Omeprazole Content 99% label claim 97%label claim LOD (Contents of PICS   0.6%   0.5% Cap Chamber) LOD(Contents of Bottle   0.6%   0.6% Chamber) Total Impurities <0.05%<0.05% Sodium Benzoate Content    99%    97% Sodium Methyl    99%    97%Parahydroxybenzoate Content pH 8.2 8.1 Buffer Capacity 2.1 mEq/ml 2.1mEq/ml

Having now fully described this disclosure, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments described herein will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification beconsidered exemplary only, with a true scope and spirit of the inventionbeing indicated by the following claims.

All patents, patent applications, and publications cited herein arefully incorporated by reference herein in their entirety.

1-14. (canceled)
 15. A storage-stable omeprazole system, the systemcomprising (i) a first mixture comprising (a) a therapeuticallyeffective amount of omeprazole, or a pharmaceutically acceptable saltthereof, (b) optionally a first desiccant, and (c) optionally a firstbuffering agent, wherein the first mixture contains a percentage ofmoisture of no more than about 2.5%; and (ii) a second mixturecomprising a second buffering agent, wherein the second mixture containsa percentage of moisture of no more than about 2.5%, wherein the firstmixture and the second mixture are stored separately from each other andare mixed together on or just before constitution with water, andwherein the system contains no sodium from a sodium-containing bufferingagent or the system contains sodium and potassium at a ratio of fromabout 1:2.6 to about 1:3.4 by weight.
 16. The storage-stable omeprazolesystem of claim 15, wherein the sodium and potassium are present at aratio of about 1:3.2 by weight.
 17. The storage-stable omeprazole systemof claim 15, wherein the first mixture and/or the second mixture has amoisture content of about 0.5% to about 1.5%.
 18. The storage-stableomeprazole system of claim wherein the first mixture comprises (b) afirst desiccant and/or the second mixture further comprises a seconddesiccant.
 19. (canceled)
 20. The storage-stable omeprazole system ofclaim 15, wherein the first mixture comprises (c) a first bufferingagent.
 21. The storage-stable omeprazole system of claim 15, wherein thefirst mixture and the second mixture are each independently in a form ofa powder, a pellet, a granule, a seed, a bead, a spheroid, amicrosphere, or a mixture thereof.
 22. The storage-stable omeprazolesystem of claim 15, wherein the omeprazole or the pharmaceuticallyacceptable salt thereof is micronized.
 23. The storage-stable omeprazolesystem of claim 15, wherein the omeprazole or the pharmaceuticallyacceptable salt thereof is a mixture of micronized and non-micronizedomeprazole or the pharmaceutically acceptable salt thereof. 24-26.(canceled)
 27. The storage-stable omeprazole system of claim 20, whereinthe first buffering agent and the second buffering agent togetherprovide a buffering capacity of about 2 mEq/ml dose of constitutedpowder with water.
 28. The storage-stable omeprazole system of claim 27,wherein the first buffering agent and the second buffering agent areeach independently selected from the group consisting of alkali metal oralkaline earth metal carbonates, bicarbonates, phosphates, citrates,borates, acetates, phthalates, tartrates, succinates, and mixturesthereof.
 29. The storage-stable omeprazole system of claim 28, whereinthe first buffering agent and the second buffering agent are eachindependently selected from the group consisting of sodium bicarbonate,potassium bicarbonate, and a mixture thereof.
 30. The storage-stableomeprazole system of claim 29, wherein the first buffering agent issodium bicarbonate.
 31. The storage-stable omeprazole system of claim29, wherein the second buffering agent is a mixture of sodiumbicarbonate and potassium bicarbonate.
 32. (canceled)
 33. Thestorage-stable omeprazole system of claim 29, wherein the first mixtureand the second mixture together comprise sodium bicarbonate andpotassium bicarbonate at a ratio of about 1:2.7 by weight.
 34. Thestorage-stable omeprazole system of claim 29, wherein the firstbuffering agent and the second buffering agent are potassiumbicarbonate.
 35. (canceled)
 36. The storage-stable omeprazole system ofclaim 15, wherein the storage-stable omeprazole system is provided in adrug delivery device suitable for multi-dose administration ofomeprazole, or the pharmaceutically acceptable salt thereof.
 37. Thestorage-stable omeprazole system of claim 36, wherein the drug deliverydevice comprises two chambers.
 38. The storage-stable omeprazole systemof claim 37, wherein the drug delivery device further comprises a meansfor releasing the contents of the first chamber into the second chamberwithout removing the cap from the drug delivery device.
 39. Thestorage-stable omeprazole system of claim 36, wherein the storage-stableomeprazole system is provided in a container body comprising a cap,wherein (i) the container body contains the second mixture and has acontainer opening formed in an upper end thereof (ii) the cap comprisesa cylindrical accommodation portion comprising the first mixture and acap portion sealing an upper end of the accommodation portion, andwherein (iii) the cap is mounted in the container opening of thecontainer body, wherein when the cap is twisted, the first mixture isreleased into the container body.
 40. (canceled)
 41. The storage-stableomeprazole system of claim 15, wherein the omeprazole system remainsstable at 25° C./60% relative humidity for at least 2 years. 42-70.(canceled)
 71. An oral pharmaceutical suspension, comprising water and apharmaceutically effective amount of a storage-stable omeprazole systemof claim 15, dispersed in the water, and wherein the suspension containsno sodium from a sodium-containing buffering agent or the suspensioncontains sodium and potassium at a ratio of from about 1:2.6 to about1:3.4 by weight.
 72. (canceled)
 73. The oral pharmaceutical suspensionof claim 71, wherein about 1 ml of the suspension contains from about 1mg to about 10 mg of omeprazole, or the pharmaceutically acceptable saltthereof.
 74. (canceled)
 75. The oral pharmaceutical suspension of claim73, wherein about 1 ml of the suspension contains about 2 mg or about 4mg of omeprazole, or the pharmaceutically acceptable salt thereof. 76.The oral pharmaceutical suspension of claim 71, wherein the first andsecond buffering agents together provide a buffering capacity of about 2mEq per ml of the suspension. 77-90. (canceled)
 91. The oralpharmaceutical suspension of claim 71, wherein the suspension isprovided in a drug delivery device suitable for multi-doseadministration of omeprazole.
 92. A method of inhibiting gastric acidsecretion, comprising administering to a subject in need thereof aneffective amount of the oral pharmaceutical suspension of claim
 71. 93.The method of claim 92, wherein the subject is a child. 94-98.(canceled)
 99. A method of preparing an oral pharmaceutical suspension,comprising combining (i) first mixture comprising (a) a therapeuticallyeffective amount of omeprazole, or a pharmaceutically acceptable saltthereof, (b) optionally a first desiccant, and (c) optionally a firstbuffering agent, wherein the first mixture contains a percentage ofmoisture of no more than about 2.5%; with (ii) a second mixturecomprising a second buffering agent, wherein the second mixture containsa percentage of moisture of no more than about 2.5%; to obtain acombined mixture, wherein the combined mixture contains no sodium from asodium-containing buffering agent or the combined mixture containssodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 byweight; and adding water to the combined mixture. 100-120. (canceled)121. A method of inhibiting gastric acid secretion, comprisingadministering to a subject in need thereof an effective amount of anoral pharmaceutical suspension comprising water, a pharmaceuticallyeffective amount of omeprazole, or a pharmaceutically acceptable saltthereof, dispersed in the water, and one or more buffering agents,wherein the suspension contains no sodium from a sodium-containingbuffering agent or the suspension contains sodium and potassium at aratio of from about 1:2.6 to about 1:3.4 by weight; and wherein the oralpharmaceutical suspension is prepared as claimed in claim
 99. 122. Theoral pharmaceutical suspension of claim 71, wherein the suspensionremains stable for at least one month at 2° C.-8° C. after constitutionwith water.
 123. A method of administering an oral pharmaceuticalsuspension to a subject in need of inhibition of gastric acid secretion,said method comprising 1) preparing an oral pharmaceutical suspension,comprising combining (i) a first mixture comprising (a) atherapeutically effective amount of omeprazole, or a pharmaceuticallyacceptable salt thereof, (b) optionally a first desiccant, and (c)optionally a first buffering agent, wherein the first mixture contains apercentage of moisture of no more than about 2.5%; with (ii) a secondmixture comprising a second buffering agent, wherein the second mixturecontains a percentage of moisture of no more than about 2.5%; to obtaina combined mixture, wherein the combined mixture contains no sodium froma sodium-containing buffering agent or the combined mixture containssodium and potassium at a ratio of from about 1:2.6 to about 1:3.4 byweight; and adding water to the combined mixture; and 2) administeringto the subject in need thereof an effective amount of the oralpharmaceutical suspension.
 124. The method of claim 123, wherein thesubject is a child.